EP2991661B1 - Composés antisens conjugués et leur utilisation - Google Patents
Composés antisens conjugués et leur utilisation Download PDFInfo
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- EP2991661B1 EP2991661B1 EP14792010.2A EP14792010A EP2991661B1 EP 2991661 B1 EP2991661 B1 EP 2991661B1 EP 14792010 A EP14792010 A EP 14792010A EP 2991661 B1 EP2991661 B1 EP 2991661B1
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- nucleoside
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Definitions
- RNAi refers to antisense-mediated gene silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC).
- RNA target function is by an occupancy-based mechanism such as is employed naturally by microRNA.
- MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. The binding of an antisense compound to a microRNA prevents that microRNA from binding to its messenger RNA targets, and thus interferes with the function of the microRNA. MicroRNA mimics can enhance native microRNA function. Certain antisense compounds alter splicing of pre-mRNA. Regardless of the specific mechanism, sequence-specificity makes antisense compounds attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of diseases.
- Antisense technology is an effective means for modulating the expression of one or more specific gene products and can therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications.
- Chemically modified nucleosides may be incorporated into antisense compounds to enhance one or more properties, such as nuclease resistance, pharmacokinetics or affinity for a target nucleic acid.
- Vitravene® flamivirsen; developed by Isis Pharmaceuticals Inc., Carlsbad, CA
- FDA U.S. Food and Drug Administration
- CMV cytomegalovirus
- an antisense oligonucleotide targeting ApoB has been approved by the U.S. Food and Drug Administration (FDA) as an adjunct treatment to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), ApoB, total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
- FDA U.S. Food and Drug Administration
- New chemical modifications have improved the potency and efficacy of antisense compounds, uncovering the potential for oral delivery as well as enhancing subcutaneous administration, decreasing potential for side effects, and leading to improvements in patient convenience.
- Chemical modifications increasing potency of antisense compounds allow administration of lower doses, which reduces the potential for toxicity, as well as decreasing overall cost of therapy. Modifications increasing the resistance to degradation result in slower clearance from the body, allowing for less frequent dosing. Different types of chemical modifications can be combined in one compound to further optimize the compound's efficacy.
- the present disclosure provides conjugated antisense compounds. In certain instances, the present disclosure provides conjugated antisense compounds comprising an antisense oligonucleotide complementary to a nucleic acid transcript. In certain instances, the present disclosure provides methods comprising contacting a cell with a conjugated antisense compound comprising an antisense oligonucleotide complementary to a nucleic acid transcript. In certain instances, the present disclosure provides methods comprising contacting a cell with a conjugated antisense compound comprising an antisense oligonucleotide and reducing the amount or activity of a nucleic acid transcript in a cell.
- the asialoglycoprotein receptor (ASGP-R) has been described previously. See e.g., Park et al., PNAS vol. 102, No. 47, pp 17125-17129 (2005 ). Such receptors are expressed on liver cells, particularly hepatocytes. Further, it has been shown that compounds comprising clusters of three N-acetylgalactosamine (GalNAc) ligands are capable of binding to the ASGP-R, resulting in uptake of the compound into the cell. See e.g., Khorev et al., Bioorganic and Medicinal Chemistry, 16, 9, pp 5216-5231 (May 2008 ).
- GalNAc N-acetylgalactosamine
- conjugates comprising such GalNAc clusters have been used to facilitate uptake of certain compounds into liver cells, specifically hepatocytes.
- certain GalNAc-containing conjugates increase activity of duplex siRNA compounds in liver cells in vivo.
- the GalNAc-containing conjugate is typically attached to the sense strand of the siRNA duplex. Since the sense strand is discarded before the antisense strand ultimately hybridizes with the target nucleic acid, there is little concern that the conjugate will interfere with activity.
- the conjugate is attached to the 3' end of the sense strand of the siRNA. See e.g., U.S. Patent 8,106,022 .
- Certain conjugate groups described herein are more active and/or easier to synthesize than conjugate groups previously described.
- conjugates are attached to single-stranded antisense compounds, including, but not limited to RNase H based antisense compounds and antisense compounds that alter splicing of a pre-mRNA target nucleic acid.
- the conjugate should remain attached to the antisense compound long enough to provide benefit (improved uptake into cells) but then should either be cleaved, or otherwise not interfere with the subsequent steps necessary for activity, such as hybridization to a target nucleic acid and interaction with RNase H or enzymes associated with splicing or splice modulation.
- This balance of properties is more important in the setting of single-stranded antisense compounds than in siRNA compounds, where the conjugate may simply be attached to the sense strand.
- conjugated single-stranded antisense compounds having improved potency in liver cells in vivo compared with the same antisense compound lacking the conjugate. Given the required balance of properties for these compounds such improved potency is surprising.
- conjugate groups herein comprise a cleavable moiety.
- the conjugate should remain on the compound long enough to provide enhancement in uptake, but after that, it is desirable for some portion or, ideally, all of the conjugate to be cleaved, releasing the parent compound (e.g., antisense compound) in its most active form.
- the cleavable moiety is a cleavable nucleoside.
- Such instances take advantage of endogenous nucleases in the cell by attaching the rest of the conjugate (the cluster) to the antisense oligonucleotide through a nucleoside via one or more cleavable bonds, such as those of a phosphodiester linkage.
- the cluster is bound to the cleavable nucleoside through a phosphodiester linkage.
- the cleavable nucleoside is attached to the antisense oligonucleotide (antisense compound) by a phosphodiester linkage.
- the conjugate group may comprise two or three cleavable nucleosides.
- Such cleavable nucleosides are linked to one another, to the antisense compound and/or to the cluster via cleavable bonds (such as those of a phosphodiester linkage).
- Certain conjugates herein do not comprise a cleavable nucleoside and instead comprise a cleavable bond. It is shown that that sufficient cleavage of the conjugate from the oligonucleotide is provided by at least one bond that is vulnerable to cleavage in the cell (a cleavable bond).
- conjugated antisense compounds are prodrugs. Such prodrugs are administered to an animal and are ultimately metabolized to a more active form. For example, conjugated antisense compounds are cleaved to remove all or part of the conjugate resulting in the active (or more active) form of the antisense compound lacking all or some of the conjugate.
- conjugates are attached at the 5' end of an oligonucleotide. Certain such 5'-conjugates are cleaved more efficiently than counterparts having a similar conjugate group attached at the 3' end. In certain embodiments, improved activity may correlate with improved cleavage. In certain instances, oligonucleotides comprising a conjugate at the 5' end have greater efficacy than oligonucleotides comprising a conjugate at the 3' end (see, for example, Examples 56, 81, 83, and 84). Further, 5'-attachment allows simpler oligonucleotide synthesis. Typically, oligonucleotides are synthesized on a solid support in the 3' to 5' direction.
- oligonucleotide typically one attaches a pre-conjugated 3' nucleoside to the solid support and then builds the oligonucleotide as usual. However, attaching that conjugated nucleoside to the solid support adds complication to the synthesis. Further, using that approach, the conjugate is then present throughout the synthesis of the oligonucleotide and can become degraded during subsequent steps or may limit the sorts of reactions and reagents that can be used.
- oligonucleotide Using the structures and techniques described herein for 5'-conjugated oligonucleotides, one can synthesize the oligonucleotide using standard automated techniques and introduce the conjugate with the final (5'-most) nucleoside or after the oligonucleotide has been cleaved from the solid support.
- conjugates and conjugated oligonucleotides are easier and/or requires few steps, and is therefore less expensive than that of conjugates previously disclosed, providing advantages in manufacturing.
- the synthesis of certain conjugate groups consists of fewer synthetic steps, resulting in increased yield, relative to conjugate groups previously described.
- Conjugate groups such as GalNAc3-10 in Example 46 and GalNAc3-7 in Example 48 are much simpler than previously described conjugates such as those described in U.S. 8,106,022 or U.S. 7,262,177 that require assembly of more chemical intermediates .
- conjugate groups having only one or two GalNAc ligands improve activity of antisense compounds. Such compounds are much easier to prepare than conjugates comprising three GalNAc ligands.
- Conjugate groups comprising one or two GalNAc ligands may be attached to any antisense compounds, including single-stranded oligonucleotides and either strand of double-stranded oligonucleotides (e.g., siRNA).
- the conjugates herein do not substantially alter certain measures of tolerability.
- conjugated antisense compounds are not more immunogenic than unconjugated parent compounds. Since potency is improved, embodiments in which tolerability remains the same (or indeed even if tolerability worsens only slightly compared to the gains in potency) have improved properties for therapy.
- conjugation allows one to alter antisense compounds in ways that have less attractive consequences in the absence of conjugation. For example, in certain instances, replacing one or more phosphorothioate linkages of a fully phosphorothioate antisense compound with phosphodiester linkages results in improvement in some measures of tolerability. For example, in certain instances, such antisense compounds having one or more phosphodiester are less immunogenic than the same compound in which each linkage is a phosphorothioate. However, in certain instances, as shown in Example 26, that same replacement of one or more phosphorothioate linkages with phosphodiester linkages also results in reduced cellular uptake and/or loss in potency.
- conjugated antisense compounds described herein tolerate such change in linkages with little or no loss in uptake and potency when compared to the conjugated full-phosphorothioate counterpart.
- oligonucleotides comprising a conjugate and at least one phosphodiester internucleoside linkage actually exhibit increased potency in vivo even relative to a full phosphorothioate counterpart also comprising the same conjugate.
- conjugated antisense compounds comprise at least one phosphodiester linkage.
- conjugation of antisense compounds herein results in increased delivery, uptake and activity in hepatocytes.
- more compound is delivered to liver tissue.
- that increased delivery alone does not explain the entire increase in activity.
- more compound enters hepatocytes.
- even that increased hepatocyte uptake does not explain the entire increase in activity.
- productive uptake of the conjugated compound is increased.
- certain embodiments of GalNAc-containing conjugates increase enrichment of antisense oligonucleotides in hepatocytes versus non-parenchymal cells. This enrichment is beneficial for oligonucleotides that target genes that are expressed in hepatocytes.
- conjugated antisense compounds herein result in reduced kidney exposure.
- concentrations of antisense oligonucleotides comprising certain embodiments of GalNAc-containing conjugates are lower in the kidney than that of antisense oligonucleotides lacking a GalNAc-containing conjugate.
- This has several beneficial therapeutic implications. For therapeutic indications where activity in the kidney is not sought, exposure to kidney risks kidney toxicity without corresponding benefit.
- high concentration in kidney typically results in loss of compound to the urine resulting in faster clearance. Accordingly for non-kidney targets, kidney accumulation is undesired.
- conjugated antisense compounds are provided having the structure:
- each such particular variable is selected independently.
- each n is selected independently, so they may or may not be the same as one another.
- nucleoside means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety.
- chemical modification means a chemical difference in a compound when compared to a naturally occurring counterpart.
- Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and internucleoside linkage modifications. In reference to an oligonucleotide, chemical modification does not include differences only in nucleobase sequence.
- furanosyl means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom.
- naturally occurring sugar moiety means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA.
- sugar moiety means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside.
- modified sugar moiety means a substituted sugar moiety or a sugar surrogate.
- substituted sugar moiety means a furanosyl that is not a naturally occurring sugar moiety.
- Substituted sugar moieties include, but are not limited to furanosyls comprising substituents at the 2'-position, the 3'-position, the 5'-position and/or the 4'-position.
- Certain substituted sugar moieties are bicyclic sugar moieties.
- 2'-substituted sugar moiety means a furanosyl comprising a substituent at the 2'-position other than H or OH. Unless otherwise indicated, a 2'-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2'-substituent of a 2'-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring.
- MOE means -OCH 2 CH 2 OCH 3 .
- 2'-F nucleoside refers to a nucleoside comprising a sugar comprising fluorine at the 2' position. Unless otherwise indicated, the fluorine in a 2'-F nucleoside is in the ribo position (replacing the OH of a natural ribose).
- sucrose surrogate means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside sub-units are capable of linking together and/or linking to other nucleosides to form an oligomeric compound which is capable of hybridizing to a complementary oligomeric compound.
- Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen.
- Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents).
- Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid).
- Sugar surrogates include without limitation morpholinos, cyclohexenyls and cyclohexitols.
- bicyclic sugar moiety means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure.
- the 4 to 7 membered ring is a sugar ring.
- the 4 to 7 membered ring is a furanosyl.
- the bridge connects the 2'-carbon and the 4'-carbon of the furanosyl.
- nucleotide means a nucleoside further comprising a phosphate linking group.
- linked nucleosides may or may not be linked by phosphate linkages and thus includes, but is not limited to “linked nucleotides.”
- linked nucleosides are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked).
- nucleobase means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified.
- unmodified nucleobase or “naturally occurring nucleobase” means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U).
- modified nucleobase means any nucleobase that is not a naturally occurring nucleobase.
- modified nucleoside means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides. Modified nucleosides comprise a modified sugar moiety and/or a modified nucleobase.
- bicyclic nucleoside or "BNA” means a nucleoside comprising a bicyclic sugar moiety.
- constrained ethyl nucleoside or “cEt” means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH(CH 3 )-O-2'bridge.
- locked nucleic acid nucleoside or "LNA” means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH 2 -O-2'bridge.
- 2'-substituted nucleoside means a nucleoside comprising a substituent at the 2'-position other than H or OH. Unless otherwise indicated, a 2'-substituted nucleoside is not a bicyclic nucleoside.
- deoxynucleoside means a nucleoside comprising 2'-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA).
- a 2'-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil).
- oligonucleotide means a compound comprising a plurality of linked nucleosides.
- an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and/or unmodified deoxyribonucleosides (DNA) and/or one or more modified nucleosides.
- oligonucleoside means an oligonucleotide in which none of the internucleoside linkages contains a phosphorus atom.
- oligonucleotides include oligonucleosides.
- modified oligonucleotide means an oligonucleotide comprising at least one modified nucleoside and/or at least one modified internucleoside linkage.
- linkage means a group of atoms that link together two or more other groups of atoms.
- nucleoside linkage means a covalent linkage between adjacent nucleosides in an oligonucleotide.
- naturally occurring internucleoside linkage means a 3' to 5' phosphodiester linkage.
- modified internucleoside linkage means any internucleoside linkage other than a naturally occurring internucleoside linkage.
- terminal internucleoside linkage means the linkage between the last two nucleosides of an oligonucleotide or defined region thereof.
- phosphorus linking group means a linking group comprising a phosphorus atom.
- Phosphorus linking groups include without limitation groups having the formula: wherein:
- nucleoside phosphorus linking group means a phosphorus linking group that directly links two nucleosides.
- non-internucleoside phosphorus linking group means a phosphorus linking group that does not directly link two nucleosides.
- a non-internucleoside phosphorus linking group links a nucleoside to a group other than a nucleoside.
- a non-internucleoside phosphorus linking group links two groups, neither of which is a nucleoside.
- neutral linking group means a linking group that is not charged.
- Further neutral linking groups include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook Eds. ACS Symposium Series 580; Chapters 3 and 4, (pp. 40-65 )).
- Further neutral linking groups include nonionic linkages comprising mixed N, O, S and CH 2 component parts.
- nucleoside neutral linking group means a neutral linking group that directly links two nucleosides.
- non-internucleoside neutral linking group means a neutral linking group that does not directly link two nucleosides.
- a non-internucleoside neutral linking group links a nucleoside to a group other than a nucleoside.
- a non-internucleoside neutral linking group links two groups, neither of which is a nucleoside.
- oligomeric compound means a polymeric structure comprising two or more substructures.
- an oligomeric compound comprises an oligonucleotide.
- an oligomeric compound comprises one or more conjugate groups and/or terminal groups.
- an oligomeric compound consists of an oligonucleotide. Oligomeric compounds also include naturally occurring nucleic acids.
- an oligomeric compound comprises a backbone of one or more linked monomeric subunits where each linked monomeric subunit is directly or indirectly attached to a heterocyclic base moiety.
- oligomeric compounds may also include monomeric subunits that are not linked to a heterocyclic base moiety, thereby providing abasic sites.
- the linkages joining the monomeric subunits, the sugar moieties or surrogates and the heterocyclic base moieties can be independently modified.
- the linkage-sugar unit, which may or may not include a heterocyclic base may be substituted with a mimetic such as the monomers in peptide nucleic acids.
- terminal group means one or more atom attached to either, or both, the 3' end or the 5' end of an oligonucleotide. In certain embodiments a terminal group is a conjugate group. In certain embodiments, a terminal group comprises one or more terminal group nucleosides.
- conjugate means an atom or group of atoms bound to an oligonucleotide or oligomeric compound.
- conjugate groups modify one or more properties of the compound to which they are attached, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and/or clearance properties.
- conjugate linker or “linker” in the context of a conjugate group means a portion of a conjugate group comprising any atom or group of atoms and which covalently link (1) an oligonucleotide to another portion of the conjugate group or (2) two or more portions of the conjugate group.
- Conjugate groups are shown herein as radicals, providing a bond for forming covalent attachment to an oligomeric compound such as an antisense oligonucleotide.
- the point of attachment on the oligomeric compound is the 3'-oxygen atom of the 3'-hydroxyl group of the 3' terminal nucleoside of the oligomeric compound.
- the point of attachment on the oligomeric compound is the 5'-oxygen atom of the 5'-hydroxyl group of the 5' terminal nucleoside of the oligomeric compound.
- the bond for forming attachment to the oligomeric compound is a cleavable bond. In certain such embodiments, such cleavable bond constitutes all or part of a cleavable moiety.
- conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and a carbohydrate cluster portion, such as a GalNAc cluster portion.
- carbohydrate cluster portion comprises: a targeting moiety and, optionally, a conjugate linker.
- the carbohydrate cluster portion is identified by the number and identity of the ligand. For example, in certain embodiments, the carbohydrate cluster portion comprises 3 GalNAc groups and is designated "GalNAc 3 ". In certain embodiments, the carbohydrate cluster portion comprises 4 GalNAc groups and is designated "GalNAc 4 ".
- carbohydrate cluster portions having specific tether, branching and conjugate linker groups
- GalNac3-1 a refers to a specific carbohydrate cluster portion of a conjugate group having 3 GalNac groups and specifically identified tether, branching and linking groups.
- Such carbohydrate cluster fragment is attached to an oligomeric compound via a cleavable moiety, such as a cleavable bond or cleavable nucleoside.
- cleavable moiety means a bond or group that is capable of being cleaved under physiological conditions.
- a cleavable moiety is cleaved inside a cell or sub-cellular compartments, such as an endosome or lysosome.
- a cleavable moiety is cleaved by endogenous enzymes, such as nucleases.
- a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds.
- a cleavable moiety is a phosphodiester linkage.
- cleavable bond means any chemical bond capable of being broken.
- a cleavable bond is selected from among: an amide, a polyamide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, a di-sulfide, or a peptide.
- carbohydrate cluster means a compound having one or more carbohydrate residues attached to a scaffold or linker group.
- a scaffold or linker group see , e.g., Maier et al., "Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Cluster for Cellular Targeting," Bioconjugate Chemistry, 2003, (14): 18-29 , or Rensen et al., “Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein Receptor," J. Med. Chem. 2004, (47): 5798-5808 , for examples of carbohydrate conjugate clusters).
- modified carbohydrate means any carbohydrate having one or more chemical modifications relative to naturally occurring carbohydrates.
- carbohydrate derivative means any compound which may be synthesized using a carbohydrate as a starting material or intermediate.
- carbohydrate means a naturally occurring carbohydrate, a modified carbohydrate, or a carbohydrate derivative.
- protecting group means any compound or protecting group known to those having skill in the art. Non-limiting examples of protecting groups may be found in " Protective Groups in Organic Chemistry", T. W. Greene, P. G. M. Wuts, ISBN 0-471-62301-6, John Wiley & Sons, Inc, New York .
- single-stranded means an oligomeric compound that is not hybridized to its complement and which lacks sufficient self-complementarity to form a stable self-duplex.
- double stranded means a pair of oligomeric compounds that are hybridized to one another or a single self-complementary oligomeric compound that forms a hairpin structure.
- a double-stranded oligomeric compound comprises a first and a second oligomeric compound.
- antisense compound means a compound comprising or consisting of an oligonucleotide at least a portion of which is complementary to a target nucleic acid to which it is capable of hybridizing, resulting in at least one antisense activity.
- antisense activity means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid.
- antisense activity includes modulation of the amount or activity of a target nucleic acid transcript (e.g. mRNA).
- antisense activity includes modulation of the splicing of pre-mRNA.
- RNase H based antisense compound means an antisense compound wherein at least some of the antisense activity of the antisense compound is attributable to hybridization of the antisense compound to a target nucleic acid and subsequent cleavage of the target nucleic acid by RNase H.
- RISC based antisense compound means an antisense compound wherein at least some of the antisense activity of the antisense compound is attributable to the RNA Induced Silencing Complex (RISC).
- RISC RNA Induced Silencing Complex
- detecting or “measuring” means that a test or assay for detecting or measuring is performed. Such detection and/or measuring may result in a value of zero. Thus, if a test for detection or measuring results in a finding of no activity (activity of zero), the step of detecting or measuring the activity has nevertheless been performed.
- detecttable and/or measureable activity means a statistically significant activity that is not zero.
- essentially unchanged means little or no change in a particular parameter, particularly relative to another parameter which changes much more.
- a parameter is essentially unchanged when it changes less than 5%.
- a parameter is essentially unchanged if it changes less than two-fold while another parameter changes at least ten-fold.
- an antisense activity is a change in the amount of a target nucleic acid.
- the amount of a non-target nucleic acid is essentially unchanged if it changes much less than the target nucleic acid does, but the change need not be zero.
- expression means the process by which a gene ultimately results in a protein.
- Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenlyation, addition of 5'-cap), and translation.
- target nucleic acid means a nucleic acid molecule to which an antisense compound is intended to hybridize to result in a desired antisense activity.
- Antisense oligonucleotides have sufficient complementarity to their target nucleic acids to allow hybridization under physiological conditions.
- nucleobase complementarity or “complementarity” when in reference to nucleobases means a nucleobase that is capable of base pairing with another nucleobase.
- adenine (A) is complementary to thymine (T).
- adenine (A) is complementary to uracil (U).
- complementary nucleobase means a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid.
- nucleobases at a certain position of an antisense compound are capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid
- the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair.
- Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity.
- non-complementary in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another.
- complementary in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides, or nucleic acids) means the capacity of such oligomeric compounds or regions thereof to hybridize to another oligomeric compound or region thereof through nucleobase complementarity.
- Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated.
- complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary).
- complementary oligomeric compounds or regions are 80% complementary.
- complementary oligomeric compounds or regions are 90% complementary.
- complementary oligomeric compounds or regions are 95% complementary.
- complementary oligomeric compounds or regions are 100% complementary.
- mismatch means a nucleobase of a first oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a second oligomeric compound, when the first and second oligomeric compound are aligned.
- first and second oligomeric compounds may be oligonucleotides.
- hybridization means the pairing of complementary oligomeric compounds (e.g., an antisense compound and its target nucleic acid). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.
- oligonucleotide or portion thereof means that each nucleobase of the oligonucleotide or portion thereof is capable of pairing with a nucleobase of a complementary nucleic acid or contiguous portion thereof.
- a fully complementary region comprises no mismatches or unhybridized nucleobases in either strand.
- percent complementarity means the percentage of nucleobases of an oligomeric compound that are complementary to an equal-length portion of a target nucleic acid. Percent complementarity is calculated by dividing the number of nucleobases of the oligomeric compound that are complementary to nucleobases at corresponding positions in the target nucleic acid by the total length of the oligomeric compound.
- percent identity means the number of nucleobases in a first nucleic acid that are the same type (independent of chemical modification) as nucleobases at corresponding positions in a second nucleic acid, divided by the total number of nucleobases in the first nucleic acid.
- modulation means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation.
- modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression.
- modulation of expression can include a change in splice site selection of pre-mRNA processing, resulting in a change in the absolute or relative amount of a particular splice-variant compared to the amount in the absence of modulation.
- chemical motif means a pattern of chemical modifications in an oligonucleotide or a region thereof. Motifs may be defined by modifications at certain nucleosides and/or at certain linking groups of an oligonucleotide.
- nucleoside motif means a pattern of nucleoside modifications in an oligonucleotide or a region thereof.
- the linkages of such an oligonucleotide may be modified or unmodified.
- motifs herein describing only nucleosides are intended to be nucleoside motifs. Thus, in such instances, the linkages are not limited.
- sugar motif means a pattern of sugar modifications in an oligonucleotide or a region thereof.
- linkage motif means a pattern of linkage modifications in an oligonucleotide or region thereof.
- the nucleosides of such an oligonucleotide may be modified or unmodified.
- motifs herein describing only linkages are intended to be linkage motifs. Thus, in such instances, the nucleosides are not limited.
- nucleobase modification motif means a pattern of modifications to nucleobases along an oligonucleotide. Unless otherwise indicated, a nucleobase modification motif is independent of the nucleobase sequence.
- sequence motif means a pattern of nucleobases arranged along an oligonucleotide or portion thereof. Unless otherwise indicated, a sequence motif is independent of chemical modifications and thus may have any combination of chemical modifications, including no chemical modifications.
- nucleoside having a modification of a first type may be an unmodified nucleoside.
- telomeres As used herein, “differently modified” mean chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified DNA nucleoside are “differently modified,” even though the DNA nucleoside is unmodified. Likewise, DNA and RNA are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified.
- nucleoside comprising a 2'-OMe modified sugar and an unmodified adenine nucleobase and a nucleoside comprising a 2'-OMe modified sugar and an unmodified thymine nucleobase are not differently modified.
- the same type of modifications refers to modifications that are the same as one another, including absence of modifications.
- two unmodified DNA nucleosides have “the same type of modification,” even though the DNA nucleoside is unmodified.
- Such nucleosides having the same type modification may comprise different nucleobases.
- separate regions means portions of an oligonucleotide wherein the chemical modifications or the motif of chemical modifications of any neighboring portions include at least one difference to allow the separate regions to be distinguished from one another.
- pharmaceutically acceptable carrier or diluent means any substance suitable for use in administering to an animal.
- a pharmaceutically acceptable carrier or diluent is sterile saline.
- such sterile saline is pharmaceutical grade saline.
- metabolic disorder means a disease or condition principally characterized by dysregulation of metabolism - the complex set of chemical reactions associated with breakdown of food to produce energy.
- cardiovascular disorder means a disease or condition principally characterized by impaired function of the heart or blood vessels.
- mono or polycyclic ring system is meant to include all ring systems selected from single or polycyclic radical ring systems wherein the rings are fused or linked and is meant to be inclusive of single and mixed ring systems individually selected from aliphatic, alicyclic, aryl, heteroaryl, aralkyl, arylalkyl, heterocyclic, heteroaryl, heteroaromatic and heteroarylalkyl.
- Such mono and poly cyclic structures can contain rings that each have the same level of saturation or each, independently, have varying degrees of saturation including fully saturated, partially saturated or fully unsaturated.
- Each ring can comprise ring atoms selected from C, N, O and S to give rise to heterocyclic rings as well as rings comprising only C ring atoms which can be present in a mixed motif such as for example benzimidazole wherein one ring has only carbon ring atoms and the fused ring has two nitrogen atoms.
- Mono or polycyclic ring systems can be attached to parent molecules using various strategies such as directly through a ring atom, fused through multiple ring atoms, through a substituent group or through a bifunctional linking moiety.
- prodrug means an inactive or less active form of a compound which, when administered to a subject, is metabolized to form the active, or more active, compound (e.g., drug).
- substituted nucleoside and “substituent group,” means an atom or group that replaces the atom or group of a named parent compound.
- a substituent of a modified nucleoside is any atom or group that differs from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2'-substuent is any atom or group at the 2'-position of a nucleoside other than H or OH).
- Substituent groups can be protected or unprotected.
- compounds of the present disclosure have substituents at one or at more than one position of the parent compound. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as an alkyl or hydrocarbyl group to a parent compound.
- substituted in reference to a chemical functional group means an atom or group of atoms that differs from the atom or a group of atoms normally present in the named functional group.
- a substituent replaces a hydrogen atom of the functional group (e.g., in certain embodiments, the substituent of a substituted methyl group is an atom or group other than hydrogen which replaces one of the hydrogen atoms of an unsubstituted methyl group).
- each R aa , R bb and R cc is, independently, H, an optionally linked chemical functional group or a further substituent group with a preferred list including without limitation, alkyl, alkenyl, alkynyl, aliphatic, alkoxy, acyl, aryl, aralkyl, heteroaryl, alicyclic, heterocyclic and heteroarylalkyl. Selected substituents within the compounds described herein are present to a recursive degree.
- alkyl means a saturated straight or branched hydrocarbon radical containing up to twenty four carbon atoms.
- alkyl groups include without limitation, methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, decyl, dodecyl and the like.
- Alkyl groups typically include from 1 to about 24 carbon atoms, more typically from 1 to about 12 carbon atoms (C 1 -C 12 alkyl) with from 1 to about 6 carbon atoms being more preferred.
- alkenyl means a straight or branched hydrocarbon chain radical containing up to twenty four carbon atoms and having at least one carbon-carbon double bond.
- alkenyl groups include without limitation, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, dienes such as 1,3-butadiene and the like.
- Alkenyl groups typically include from 2 to about 24 carbon atoms, more typically from 2 to about 12 carbon atoms with from 2 to about 6 carbon atoms being more preferred.
- Alkenyl groups as used herein may optionally include one or more further substituent groups.
- alkynyl means a straight or branched hydrocarbon radical containing up to twenty four carbon atoms and having at least one carbon-carbon triple bond.
- alkynyl groups include, without limitation, ethynyl, 1-propynyl, 1-butynyl, and the like.
- Alkynyl groups typically include from 2 to about 24 carbon atoms, more typically from 2 to about 12 carbon atoms with from 2 to about 6 carbon atoms being more preferred.
- Alkynyl groups as used herein may optionally include one or more further substituent groups.
- acyl means a radical formed by removal of a hydroxyl group from an organic acid and has the general Formula -C(O)-X where X is typically aliphatic, alicyclic or aromatic. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates, aliphatic phosphates and the like. Acyl groups as used herein may optionally include further substituent groups.
- alicyclic means a cyclic ring system wherein the ring is aliphatic.
- the ring system can comprise one or more rings wherein at least one ring is aliphatic.
- Preferred alicyclics include rings having from about 5 to about 9 carbon atoms in the ring.
- Alicyclic as used herein may optionally include further substituent groups.
- aliphatic means a straight or branched hydrocarbon radical containing up to twenty four carbon atoms wherein the saturation between any two carbon atoms is a single, double or triple bond.
- An aliphatic group preferably contains from 1 to about 24 carbon atoms, more typically from 1 to about 12 carbon atoms with from 1 to about 6 carbon atoms being more preferred.
- the straight or branched chain of an aliphatic group may be interrupted with one or more heteroatoms that include nitrogen, oxygen, sulfur and phosphorus.
- Such aliphatic groups interrupted by heteroatoms include without limitation, polyalkoxys, such as polyalkylene glycols, polyamines, and polyimines. Aliphatic groups as used herein may optionally include further substituent groups.
- alkoxy means a radical formed between an alkyl group and an oxygen atom wherein the oxygen atom is used to attach the alkoxy group to a parent molecule.
- alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like.
- Alkoxy groups as used herein may optionally include further substituent groups.
- aminoalkyl means an amino substituted C 1 -C 12 alkyl radical.
- the alkyl portion of the radical forms a covalent bond with a parent molecule.
- the amino group can be located at any position and the aminoalkyl group can be substituted with a further substituent group at the alkyl and/or amino portions.
- aralkyl and arylalkyl mean an aromatic group that is covalently linked to a C 1 -C 12 alkyl radical.
- the alkyl radical portion of the resulting aralkyl (or arylalkyl) group forms a covalent bond with a parent molecule. Examples include without limitation, benzyl, phenethyl and the like.
- Aralkyl groups as used herein may optionally include further substituent groups attached to the alkyl, the aryl or both groups that form the radical group.
- aryl and aromatic mean a mono- or polycyclic carbocyclic ring system radicals having one or more aromatic rings.
- aryl groups include without limitation, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
- Preferred aryl ring systems have from about 5 to about 20 carbon atoms in one or more rings.
- Aryl groups as used herein may optionally include further substituent groups.
- heteroaryl and “heteroaromatic,” mean a radical comprising a mono- or polycyclic aromatic ring, ring system or fused ring system wherein at least one of the rings is aromatic and includes one or more heteroatoms. Heteroaryl is also meant to include fused ring systems including systems where one or more of the fused rings contain no heteroatoms. Heteroaryl groups typically include one ring atom selected from sulfur, nitrogen or oxygen.
- heteroaryl groups include without limitation, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl and the like.
- Heteroaryl radicals can be attached to a parent molecule directly or through a linking moiety such as an aliphatic group or hetero atom.
- Heteroaryl groups as used herein may optionally include further substituent groups.
- conjugate compound means any atoms, group of atoms, or group of linked atoms suitable for use as a conjugate group.
- conjugate compounds may possess or impart one or more properties, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and/or clearance properties.
- double-stranded refers to two separate oligomeric compounds that are hybridized to one another.
- Such double stranded compounds may have one or more or non-hybridizing nucleosides at one or both ends of one or both strands (overhangs) and/or one or more internal non-hybridizing nucleosides (mismatches) provided there is sufficient complementarity to maintain hybridization under physiologically relevant conditions.
- the invention provides conjugated antisense compounds comprising antisense oligonucleoitdes and a conjugate.
- the invention provides antisense oligonucleotides.
- antisense oligonucleotides comprise linked nucleosides, each nucleoside comprising a sugar moiety and a nucleobase.
- the structure of such antisense oligonucleotides may be considered in terms of chemical features (e.g., modifications and patterns of modifications) and nucleobase sequence (e.g., sequence of antisense oligonucleotide, idenity and sequence of target nucleic acid).
- antisense oligonucleotide comprise one or more modification.
- antisense oligonucleotides comprise one or more modified nucleosides and/or modified internucleoside linkages.
- modified nucleosides comprise a modifed sugar moirty and/or modifed nucleobase.
- compounds of the disclosure comprise one or more modifed nucleosides comprising a modifed sugar moiety.
- Such compounds comprising one or more sugar-modified nucleosides may have desirable properties, such as enhanced nuclease stability or increased binding affinity with a target nucleic acid relative to an oligonucleotide comprising only nucleosides comprising naturally occurring sugar moieties.
- modified sugar moieties are substitued sugar moieties.
- modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of substituted sugar moieties.
- modified sugar moieties are substituted sugar moieties comprising one or more non-bridging sugar substituent, including but not limited to substituents at the 2' and/or 5' positions.
- sugar substituents suitable for the 2'-position include, but are not limited to: 2'-F, 2'-OCH 3 ("OMe” or "O-methyl"), and 2'-O(CH 2 ) 2 OCH 3 (“MOE").
- sugar substituents at the 5'-position include, but are not limited to:, 5'-methyl (R or S); 5'-vinyl, and 5'-methoxy.
- substituted sugars comprise more than one non-bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties ( see , e . g ., PCT International Application WO 2008/101157 , for additional 5', 2'-bis substituted sugar moieties and nucleosides).
- Nucleosides comprising 2'-substituted sugar moieties are referred to as 2'-substituted nucleosides.
- These 2'-substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl and alkynyl.
- a 2'- substituted nucleoside comprises a sugar moiety comprising a 2'-substituent group selected from F, O-CH 3 , and OCH 2 CH 2 OCH 3 .
- Certain modifed sugar moieties comprise a bridging sugar substituent that forms a second ring resulting in a bicyclic sugar moiety.
- the bicyclic sugar moiety comprises a bridge between the 4' and the 2' furanose ring atoms.
- Examples of such 4' to 2' sugar substituents include, but are not limited to: -[C(R a )(R b )] n -, -[C(R a )(R b )] n -O-, -C(R a R b )-N(R)-O- or, -C(R a R b )-O-N(R)-; 4'-CH 2 -2', 4'-(CH 2 ) 2 -2', 4'-(CH 2 ) 3 -2',.
- Bicyclic nucleosides include, but are not limited to, (A) ⁇ -L-Methyleneoxy (4'-CH 2 -O-2') BNA , (B) ⁇ -D-Methyleneoxy (4'-CH 2 -O-2') BNA (also referred to as locked nucleic acid or LNA), (C) Ethyleneoxy (4'-(CH 2 ) 2 -O-2') BNA, (D) Aminooxy (4'-CH 2 -O-N(R)-2') BNA, (E) Oxyamino (4'-CH 2 -N(R)-O-2') BNA, (F) Methyl(methyleneoxy) (4'-CH(CH 3 )-O-2') BNA (also referred to as constrained ethyl or cEt), (G) methylene-thio (4'-CH 2 -
- bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration.
- a nucleoside comprising a 4'-2' methylene-oxy bridge may be in the ⁇ -L configuration or in the ⁇ -D configuration.
- ⁇ -L-methyleneoxy (4'-CH 2 -O-2') bicyclic nucleosides have been incorporated into antisense oligonucleotides that showed antisense activity ( Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372 ).
- substituted sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5'-substituted and 4'-2' bridged sugars), ( see , PCT International Application WO 2007/134181 , published on 11/22/07, wherein LNA is substituted with, for example, a 5'-methyl or a 5'-vinyl group).
- bridging sugar substituent e.g., 5'-substituted and 4'-2' bridged sugars
- modified sugar moieties are sugar surrogates.
- the oxygen atom of the naturally occuring sugar is substituted, e.g., with a sulfer, carbon or nitrogen atom.
- such modified sugar moiety also comprises bridging and/or non-bridging substituents as described above.
- certain sugar surrogates comprise a 4'-sulfer atom and a substitution at the 2'-position ( see , e . g ., published U.S. Patent Application US2005/0130923, published on June 16, 2005 ) and/or the 5' position.
- carbocyclic bicyclic nucleosides having a 4'-2' bridge have been described (see , e . g ., Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443 and Albaek et al., J. Org. Chem., 2006, 71, 7731-7740 ).
- sugar surrogates comprise rings having other than 5-atoms.
- a sugar surrogate comprises a morphlino. Morpholino compounds and their use in oligomeric compounds has been reported in numerous patents and published articles (see for example: Braasch et al., Biochemistry, 2002, 41, 4503-4510 ; and U.S. Patents 5,698,685 ; 5,166,315 ; 5,185,444 ; and 5,034,506 ).
- morpholino means a sugar surrogate having the following structure:
- morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are refered to herein as "modifed morpholinos.”
- a sugar surrogate comprises a six-membered tetrahydropyran.
- Such tetrahydropyrans may be further modified or substituted.
- Nucleosides comprising such modified tetrahydropyrans include, but are not limited to, hexitol nucleic acid (HNA), anitol nucleic acid (ANA), manitol nucleic acid (MNA) ( see Leumann, CJ. Bioorg. & Med. Chem. (2002) 10:841-854 ), fluoro HNA (F-HNA), and those compounds having Formula VI: wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula VI:
- the modified THP nucleosides of Formula VI are provided wherein q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 are each H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is other than H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is methyl. In certain embodiments, THP nucleosides of Formula VI are provided wherein one of R 1 and R 2 is F. In certain embodiments, R 1 is fluoro and R 2 is H, R 1 is methoxy and R 2 is H, and R 1 is methoxyethoxy and R 2 is H.
- Patent Application US2005-0130923 published on June 16, 2005 or alternatively 5'-substitution of a bicyclic nucleic acid (see PCT International Application WO 2007/134181 , published on 11/22/07 wherein a 4'-CH 2 -O-2' bicyclic nucleoside is further substituted at the 5' position with a 5'-methyl or a 5'-vinyl group).
- PCT International Application WO 2007/134181 published on 11/22/07 wherein a 4'-CH 2 -O-2' bicyclic nucleoside is further substituted at the 5' position with a 5'-methyl or a 5'-vinyl group.
- carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described ( see , e.g., Srivastava et al., J. Am. Chem. Soc. 2007, 129(26), 8362-8379 ).
- the present disclosure provides oligonucleotides comprising modified nucleosides.
- modified nucleotides may include modified sugars, modified nucleobases, and/or modified linkages. The specific modifications are selected such that the resulting oligonucleotides possess desireable characteristics.
- oligonucleotides comprise one or more RNA-like nucleosides. In certain embodiments, oligonucleotides comprise one or more DNA-like nucleotides.
- nucleosides of the present disclosure comprise one or more unmodified nucleobases. In certain embodiments, nucleosides of the present disclosure comprise one or more modifed nucleobases.
- modified nucleobases are selected from: universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases as defined herein.
- 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil; 5-propynylcytosine; 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (-C C-CH 3 ) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo
- nucleobases include tricyclic pyrimidines such as phenoxazine cytidine([5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g.
- nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in United States Patent No.
- the present disclosure provides oligonucleotides comprising linked nucleosides.
- nucleosides may be linked together using any internucleoside linkage.
- the two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom.
- Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters (PO), phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates (PS).
- Non-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH 2 -N(CH 3 )-O-CH 2 -), thiodiester (-O-C(O)-S-), thionocarbamate (-O-C(O)(NH)-S-); siloxane (-O-Si(H) 2 -O-); and N,N'-dimethylhydrazine (-CH 2 -N(CH 3 )-N(CH 3 )-).
- Modified linkages compared to natural phosphodiester linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide.
- internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers.
- Representative chiral linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.
- oligonucleotides described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), ⁇ or ⁇ such as for sugar anomers, or as (D) or (L) such as for amino acids etc. Included in the antisense compounds provided herein are all such possible isomers, as well as their racemic and optically pure forms.
- Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65 ). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH 2 component parts.
- antisense oligonucleotides comprise one or more modified nucleoside (e.g., nucleoside comprising a modified sugar and/or modified nucleobase) and/or one or more modified internucleoside linkage.
- modified nucleoside e.g., nucleoside comprising a modified sugar and/or modified nucleobase
- internucleoside linkage e.g., a modified internucleoside linkage.
- the pattern of such modifications on an oligonucleotide is referred to herein as a motif.
- sugar, nucleobase, and linkage motifs are independent of one another.
- oligonucleotides comprise one or more type of modified sugar moieties and/or naturally occurring sugar moieties arranged along an oligonucleotide or region thereof in a defined pattern or sugar modification motif.
- Such motifs may include any of the sugar modifications discussed herein and/or other known sugar modifications.
- the oligonucleotides comprise or consist of a region having a gapmer sugar motif, which comprises two external regions or "wings" and a central or internal region or "gap."
- the three regions of a gapmer sugar motif (the 5'-wing, the gap, and the 3'-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap.
- the sugar moieties of the nucleosides of each wing that are closest to the gap differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap.
- the sugar moieties within the gap are the same as one another.
- the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap.
- the sugar motifs of the two wings are the same as one another (symmetric sugar gapmer).
- the sugar motifs of the 5'-wing differs from the sugar motif of the 3'-wing (asymmetric sugar gapmer).
- the 5'- wing of a gapmer consists of 1 to 8 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 1 to 7 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 6 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 1 to 5 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 2 to 5 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 3 to 5 linked nucleosides.
- the 5'- wing of a gapmer consists of 4 or 5 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 3 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 1 or 2 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 2 to 4 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 2 or 3 linked nucleosides.
- the 5'- wing of a gapmer consists of 3 or 4 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 1 nucleoside. In certain embodiments, the 5'- wing of a gapmer consists of 2 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 3 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 4 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 5 linked nucleosides. In certain embodiments, the 5'- wing of a gapmer consists of 6 linked nucleosides.
- the 5'- wing of a gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the 5'- wing of a gapmer comprises at least two bicyclic nucleosides. In certain embodiments, the 5'- wing of a gapmer comprises at least three bicyclic nucleosides. In certain embodiments, the 5'- wing of a gapmer comprises at least four bicyclic nucleosides. In certain embodiments, the 5'- wing of a gapmer comprises at least one constrained ethyl nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one LNA nucleoside.
- each nucleoside of the 5'-wing of a gapmer is a bicyclic nucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a constrained ethyl nucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a LNA nucleoside.
- the 5'- wing of a gapmer comprises at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'- wing of a gapmer comprises at least one 2'-substituted nucleoside. In certain embodiments, the 5'- wing of a gapmer comprises at least one 2'-MOE nucleoside. In certain embodiments, the 5'- wing of a gapmer comprises at least one 2'-OMe nucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a non-bicyclic modified nucleoside.
- each nucleoside of the 5'- wing of a gapmer is a 2'-substituted nucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a 2'-MOE nucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a 2'-OMe nucleoside.
- the 5'- wing of a gapmer comprises at least one 2'-deoxynucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a 2'-deoxynucleoside. In a certain embodiments, the 5'- wing of a gapmer comprises at least one ribonucleoside. In certain embodiments, each nucleoside of the 5'- wing of a gapmer is a ribonucleoside. In certain embodiments, one, more than one, or each of the nucleosides of the 5'- wing is an RNA-like nucleoside.
- the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-deoxynucleoside.
- the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-deoxynucleoside.
- the 3'- wing of a gapmer consists of 1 to 8 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 1 to 7 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 6 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 1 to 5 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 2 to 5 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 3 to 5 linked nucleosides.
- the 3'- wing of a gapmer consists of 4 or 5 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 3 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 1 or 2 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 2 to 4 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 2 or 3 linked nucleosides.
- the 3'- wing of a gapmer consists of 3 or 4 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 1 nucleoside. In certain embodiments, the 3'- wing of a gapmer consists of 2 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 3 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 4 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 5 linked nucleosides. In certain embodiments, the 3'- wing of a gapmer consists of 6 linked nucleosides.
- the 3'- wing of a gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the 3'- wing of a gapmer comprises at least one constrained ethyl nucleoside. In certain embodiments, the 3'- wing of a gapmer comprises at least one LNA nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a bicyclic nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a constrained ethyl nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a LNA nucleoside.
- the 3'- wing of a gapmer comprises at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'- wing of a gapmer comprises at least two non-bicyclic modified nucleosides. In certain embodiments, the 3'- wing of a gapmer comprises at least three non-bicyclic modified nucleosides. In certain embodiments, the 3'- wing of a gapmer comprises at least four non-bicyclic modified nucleosides. In certain embodiments, the 3'- wing of a gapmer comprises at least one 2'-substituted nucleoside.
- the 3'- wing of a gapmer comprises at least one 2'-MOE nucleoside. In certain embodiments, the 3'- wing of a gapmer comprises at least one 2'-OMe nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a non-bicyclic modified nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a 2'-substituted nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a 2'-MOE nucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a 2'-OMe nucleoside.
- the 3'- wing of a gapmer comprises at least one 2'-deoxynucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a 2'-deoxynucleoside. In a certain embodiments, the 3'- wing of a gapmer comprises at least one ribonucleoside. In certain embodiments, each nucleoside of the 3'- wing of a gapmer is a ribonucleoside. In certain embodiments, one, more than one, or each of the nucleosides of the 5'- wing is an RNA-like nucleoside.
- the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-substituted nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'-substituted nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-substituted nucleoside, and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-MOE nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'-MOE nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-MOE nucleoside, and at least one 2'-deoxynucleoside.
- the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-OMe nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'-OMe nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-OMe nucleoside, and at least one 2'-deoxynucleoside.
- the gap of a gapmer consists of 6 to 20 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 15 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 12 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 or 7 linked nucleosides.
- the gap of a gapmer consists of 7 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 to 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 or 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 8 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 8 or 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 linked nucleosides.
- the gap of a gapmer consists of 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 11 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 12 linked nucleosides.
- each nucleoside of the gap of a gapmer is a 2'-deoxynucleoside.
- the gap comprises one or more modified nucleosides.
- each nucleoside of the gap of a gapmer is a 2'-deoxynucleoside or is a modified nucleoside that is "DNA-like.”
- DNA-like means that the nucleoside has similar characteristics to DNA, such that a duplex comprising the gapmer and an RNA molecule is capable of activating RNase H. For example, under certain conditions, 2'-(ara)-F have been shown to support RNase H activation, and thus is DNA-like.
- one or more nucleosides of the gap of a gapmer is not a 2'-deoxynucleoside and is not DNA-like. In certain such embodiments, the gapmer nonetheless supports RNase H activation (e.g., by virtue of the number or placement of the non-DNA nucleosides).
- gaps comprise a stretch of unmodified 2'-deoxynucleoside interrupted by one or more modified nucleosides, thus resulting in three sub-regions (two stretches of one or more 2'-deoxynucleosides and a stretch of one or more interrupting modified nucleosides).
- no stretch of unmodified 2'-deoxynucleosides is longer than 5, 6, or 7 nucleosides.
- such short stretches is achieved by using short gap regions.
- short stretches are achieved by interrupting a longer gap region.
- the gap comprises one or more modified nucleosides. In certain embodiments, the gap comprises one or more modified nucleosides selected from among cEt, FHNA, LNA, and 2-thio-thymidine. In certain embodiments, the gap comprises one modified nucleoside. In certain embodiments, the gap comprises a 5'-substituted sugar moiety selected from among 5'-Me, and 5'-(R)-Me. In certain embodiments, the gap comprises two modified nucleosides. In certain embodiments, the gap comprises three modified nucleosides. In certain embodiments, the gap comprises four modified nucleosides. In certain embodiments, the gap comprises two or more modified nucleosides and each modified nucleoside is the same. In certain embodiments, the gap comprises two or more modified nucleosides and each modified nucleoside is different.
- the gap comprises one or more modified linkages. In certain embodiments, the gap comprises one or more methyl phosphonate linkages. In certain embodiments the gap comprises two or more modified linkages. In certain embodiments, the gap comprises one or more modified linkages and one or more modified nucleosides. In certain embodiments, the gap comprises one modified linkage and one modified nucleoside. In certain embodiments, the gap comprises two modified linkages and two or more modified nucleosides.
- oligonucleotides comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides of the present disclosure comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate internucleoside linkages.
- each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate.
- the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 7 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 9 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages.
- the oligonucleotide comprises at least 11 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 12 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 13 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 14 phosphorothioate internucleoside linkages.
- the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 7 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 9 consecutive phosphorothioate internucleoside linkages.
- the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3' end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the oligonucleotide comprises less than 15 phosphorothioate internucleoside linkages.
- the oligonucleotide comprises less than 14 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 13 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 12 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 11 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 10 phosphorothioate internucleoside linkages.
- the oligonucleotide comprises less than 9 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 7 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 5 phosphorothioate internucleoside linkages.
- oligonucleotides comprise chemical modifications to nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or nucleobases modification motif.
- nucleobase modifications are arranged in a gapped motif.
- nucleobase modifications are arranged in an alternating motif.
- each nucleobase is modified.
- none of the nucleobases is chemically modified.
- oligonucleotides comprise a block of modified nucleobases.
- the block is at the 3'-end of the oligonucleotide.
- the block is within 3 nucleotides of the 3'-end of the oligonucleotide.
- the block is at the 5'-end of the oligonucleotide. In certain embodiments the block is within 3 nucleotides of the 5'-end of the oligonucleotide.
- nucleobase modifications are a function of the natural base at a particular position of an oligonucleotide.
- each purine or each pyrimidine in an oligonucleotide is modified.
- each adenine is modified.
- each guanine is modified.
- each thymine is modified.
- each cytosine is modified.
- each uracil is modified.
- cytosine moieties in an oligonucleotide are 5-methyl cytosine moieties.
- 5-methyl cytosine is not a "modified nucleobase.” Accordingly, unless otherwise indicated, unmodified nucleobases include both cytosine residues having a 5-methyl and those lacking a 5 methyl. In certain embodiments, the methylation state of all or some cytosine nucleobases is specified.
- chemical modifications to nucleobases comprise attachment of certain conjugate groups to nucleobases.
- each purine or each pyrimidine in an oligonucleotide may be optionally modified to comprise a conjugate group.
- oligonucleotides of any of a variety of ranges of lengths.
- oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number of nucleosides in the range.
- X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X ⁇ Y.
- the oligonucleotide may consist of 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 21, 8 to 22, 8 to 23, 8 to 24, 8 to 25, 8 to 26, 8 to 27, 8 to 28, 8 to 29, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 21, 9 to 22, 9 to 23, 9 to 24, 9 to 25, 9 to 26, 9 to 27, 9 to 28, 9 to 29, 9 to 30, 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 21, 10 to 22, 10 to 23, 10 to 24, 10 to 25, 10 to 26, 10 to 27, 10 to 28, 10 to 29, 10 to 30, 11 to 12, 11 to 13, 11 to 14, 11 to 15, 11 to 16, 11 to 17, 11 to 18, 11 to 19, 11 to 20, 11 to 21, 11 to 22, 11 to 23, 11 to 24, 11 to 25, 11 to 26, 11 to 26, 11 to 29, 11 to
- an oligonucleotide comprising 8-30 nucleosides excludes oligonucleotides having 31 nucleosides, but, unless otherwise indicated, such an oligonucleotide may further comprise, for example one or more conjugate groups, terminal groups, or other substituents.
- an oligonucleotide is described by an overall length range and by regions having specified lengths, and where the sum of specified lengths of the regions is less than the upper limit of the overall length range, the oligonucleotide may have additional nucleosides, beyond those of the specified regions, provided that the total number of nucleosides does not exceed the upper limit of the overall length range.
- the chemical structural features of antisense oligonucleotides are characterized by their sugar motif, internucleoside linkage motif, nucleobase modification motif and overall length. In certain embodiments, such parameters are each independent of one another. Thus, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. Thus, the internucleoside linkages within the wing regions of a sugar-gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region.
- sugar-gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications.
- modified nucleobase independent of the gapmer pattern of the sugar modifications.
- One of skill in the art will appreciate that such motifs may be combined to create a variety of oligonucleotides.
- the selection of internucleoside linkage and nucleoside modification are not independent of one another.
- the invention provides antisense oligonucleotides having a sequence complementary to a target nucleic acid.
- antisense compounds are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity.
- antisense compounds specifically hybridize to one or more target nucleic acid.
- a specifically hybridizing antisense compound has a nucleobase sequence comprising a region having sufficient complementarity to a target nucleic acid to allow hybridization and result in antisense activity and insufficient complementarity to any non-target so as to avoid or reduce non-specific hybridization to non-target nucleic acid sequences under conditions in which specific hybridization is desired (e.g., under physiological conditions for in vivo or therapeutic uses, and under conditions in which assays are performed in the case of in vitro assays).
- oligonucleotides are selective between a target and non-target, even though both target and non-target comprise the target sequence. In such embodiments, selectivity may result from relative accessibility of the target region of one nucleic acid molecule compared to the other.
- the present disclosure provides antisense compounds comprising oligonucleotides that are fully complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are 95% complementary to the target nucleic acid. In certain embodiments, such oligonucleotides are 90% complementary to the target nucleic acid.
- such oligonucleotides are 85% complementary to the target nucleic acid. In certain embodiments, such oligonucleotides are 80% complementary to the target nucleic acid. In certain embodiments, an antisense compound comprises a region that is fully complementary to a target nucleic acid and is at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain such embodiments, the region of full complementarity is from 6 to 14 nucleobases in length.
- oligonucleotides comprise a hybridizing region and a terminal region.
- the hybridizing region consists of 12-30 linked nucleosides and is fully complementary to the target nucleic acid.
- the hybridizing region includes one mismatch relative to the target nucleic acid.
- the hybridizing region includes two mismatches relative to the target nucleic acid.
- the hybridizing region includes three mismatches relative to the target nucleic acid.
- the terminal region consists of 1-4 terminal nucleosides.
- the terminal nucleosides are at the 3' end. In certain embodiments, one or more of the terminal nucleosides are not complementary to the target nucleic acid.
- Antisense mechanisms include any mechanism involving the hybridization of an oligonucleotide with target nucleic acid, wherein the hybridization results in a biological effect. In certain embodiments, such hybridization results in either target nucleic acid degradation or occupancy with concomitant inhibition or stimulation of the cellular machinery involving, for example, translation, transcription, or splicing of the target nucleic acid.
- RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are "DNA-like" elicit RNase H activity in mammalian cells. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of DNA-like oligonucleotide-mediated inhibition of gene expression.
- a conjugate group comprises a cleavable moiety. In certain embodiments, a conjugate group comprises one or more cleavable bond. In certain embodiments, a conjugate group comprises a linker. In certain embodiments, a linker comprises a protein binding moiety. In certain embodiments, a conjugate group comprises a cell-targeting moiety (also referred to as a cell-targeting group). In certain embodiments a cell-targeting moiety comprises a branching group. In certain embodiments, a cell-targeting moiety comprises one or more tethers. In certain embodiments, a cell-targeting moiety comprises a carbohydrate or carbohydrate cluster.
- a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety comprises a cleavable bond. In certain embodiments, the conjugate group comprises a cleavable moiety. In certain such embodiments, the cleavable moiety attaches to the antisense oligonucleotide. In certain such embodiments, the cleavable moiety attaches directly to the cell-targeting moiety. In certain such embodiments, the cleavable moiety attaches to the conjugate linker. In certain embodiments, the cleavable moiety comprises a phosphate or phosphodiester.
- the cleavable moiety is a cleavable nucleoside or nucleoside analog.
- the nucleoside or nucleoside analog comprises an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine.
- the cleavable moiety is a nucleoside comprising an optionally protected heterocyclic base selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine.
- the cleavable moiety is 2'-deoxy nucleoside that is attached to the 3' position of the antisense oligonucleotide by a phosphodiester linkage and is attached to the linker by a phosphodiester or phosphorothioate linkage. In certain embodiments, the cleavable moiety is 2'-deoxy adenosine that is attached to the 3' position of the antisense oligonucleotide by a phosphodiester linkage and is attached to the linker by a phosphodiester or phosphorothioate linkage.
- the cleavable moiety is 2'-deoxy adenosine that is attached to the 3' position of the antisense oligonucleotide by a phosphodiester linkage and is attached to the linker by a phosphodiester linkage.
- the cleavable moiety is attached to the 3' position of the antisense oligonucleotide. In certain embodiments, the cleavable moiety is attached to the 5' position of the antisense oligonucleotide. In certain embodiments, the cleavable moiety is attached to a 2' position of the antisense oligonucleotide. In certain embodiments, the cleavable moiety is attached to the antisense oligonucleotide by a phosphodiester linkage. In certain embodiments, the cleavable moiety is attached to the linker by either a phosphodiester or a phosphorothioate linkage. In certain embodiments, the cleavable moiety is attached to the linker by a phosphodiester linkage. In certain embodiments, the conjugate group does not include a cleavable moiety.
- the cleavable moiety is cleaved after the complex has been administered to an animal only after being internalized by a targeted cell. Inside the cell the cleavable moiety is cleaved thereby releasing the active antisense oligonucleotide. While not wanting to be bound by theory it is believed that the cleavable moiety is cleaved by one or more nucleases within the cell. In certain embodiments, the one or more nucleases cleave the phosphodiester linkage between the cleavable moiety and the linker.
- the cleavable moiety has a structure selected from among the following: wherein each of Bx, Bx 1 , Bx 2 , and Bx 3 is independently a heterocyclic base moiety. In certain embodiments, the cleavable moiety has a structure selected from among the following:
- the conjugate groups comprise a linker.
- the linker is covalently bound to the cleavable moiety.
- the linker is covalently bound to the antisense oligonucleotide.
- the linker is covalently bound to a cell-targeting moiety.
- the linker further comprises a covalent attachment to a solid support.
- the linker further comprises a covalent attachment to a protein binding moiety.
- the linker further comprises a covalent attachment to a solid support and further comprises a covalent attachment to a protein binding moiety.
- the linker includes multiple positions for attachment of tethered ligands. In certain embodiments, the linker includes multiple positions for attachment of tethered ligands and is not attached to a branching group. In certain embodiments, the linker further comprises one or more cleavable bond. In certain embodiments, the conjugate group does not include a linker.
- the linker includes at least a linear group comprising groups selected from alkyl, amide, disulfide, polyethylene glycol, ether, thioether (-S-) and hydroxylamino (-O-N(H)-) groups.
- the linear group comprises groups selected from alkyl, amide and ether groups.
- the linear group comprises groups selected from alkyl and ether groups.
- the linear group comprises at least one phosphorus linking group.
- the linear group comprises at least one phosphodiester group.
- the linear group includes at least one neutral linking group.
- the linear group is covalently attached to the cell-targeting moiety and the cleavable moiety. In certain embodiments, the linear group is covalently attached to the cell-targeting moiety and the antisense oligonucleotide. In certain embodiments, the linear group is covalently attached to the cell-targeting moiety, the cleavable moiety and a solid support. In certain embodiments, the linear group is covalently attached to the cell-targeting moiety, the cleavable moiety, a solid support and a protein binding moiety. In certain embodiments, the linear group includes one or more cleavable bond.
- the linker includes the linear group covalently attached to a scaffold group.
- the scaffold includes a branched aliphatic group comprising groups selected from alkyl, amide, disulfide, polyethylene glycol, ether, thioether and hydroxylamino groups.
- the scaffold includes a branched aliphatic group comprising groups selected from alkyl, amide and ether groups.
- the scaffold includes at least one mono or polycyclic ring system.
- the scaffold includes at least two mono or polycyclic ring systems.
- the linear group is covalently attached to the scaffold group and the scaffold group is covalently attached to the cleavable moiety and the linker.
- the linear group is covalently attached to the scaffold group and the scaffold group is covalently attached to the cleavable moiety, the linker and a solid support. In certain embodiments, the linear group is covalently attached to the scaffold group and the scaffold group is covalently attached to the cleavable moiety, the linker and a protein binding moiety. In certain embodiments, the linear group is covalently attached to the scaffold group and the scaffold group is covalently attached to the cleavable moiety, the linker, a protein binding moiety and a solid support. In certain embodiments, the scaffold group includes one or more cleavable bond.
- the linker includes a protein binding moiety.
- the protein binding moiety is a lipid such as for example including but not limited to cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, 03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine), a vitamin (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), a peptide, a carbohydrate (e.g., monosaccharide), a vitamin (e
- a linker has a structure selected from among: wherein each n is, independently, from 1 to 20; and p is from 1 to 6.
- a linker has a structure selected from among: wherein each n is, independently, from 1 to 20.
- a linker has a structure selected from among: and wherein n is from 1 to 20.
- a linker has a structure selected from among: wherein each L is, independently, a phosphorus linking group or a neutral linking group; and each n is, independently, from 1 to 20.
- a linker has a structure selected from among:
- a linker has a structure selected from among:
- a linker has a structure selected from among:
- a linker has a structure selected from among: wherein n is from 1 to 20.
- a linker has a structure selected from among:
- a linker has a structure selected from among:
- a linker has a structure selected from among:
- the conjugate linker has the structure:
- the conjugate linker has the structure:
- a linker has a structure selected from among:
- a linker has a structure selected from among: wherein each n is independently, 0, 1, 2, 3, 4, 5, 6, or 7.
- the conjugate groups of the present invention comprise cell-targeting moieties. Certain such cell-targeting moieties increase cellular uptake of antisense compounds.
- the cell-targeting moieties comprise a branching group, threetethers, and three ligands.
- the conjugate groups of the present invention comprise a targeting moiety comprising a branching group and threetethered ligands.
- the branching group attaches the conjugate linker.
- the branching group attaches the cleavable moiety.
- the branching group attaches the antisense oligonucleotide.
- the branching group is covalently attached to the linker and each of the tethered ligands.
- a branching group has a structure selected from among:
- a branching group has a structure selected from among:
- a branching group has a structure selected from among:
- the branching group of the present invention has the structure:
- the conjugate groups of the present invention comprise three tethers covalently attached to the branching group.
- the tether is attached to the branching group through an ether group.
- the tether is attached to the ligand through an ether group.
- the tether of the present invention has the structure:
- each ligand of the present invention is covalently attached to a tether.
- each ligand is selected to have an affinity for at least one type of receptor on a target cell.
- ligands are selected that have an affinity for at least one type of receptor on the surface of a mammalian liver cell.
- ligands are selected that have an affinity for the hepatic asialoglycoprotein receptor (ASGP-R).
- ASGP-R hepatic asialoglycoprotein receptor
- each ligand is a carbohydrate.
- Each ligand of the invention is N-acetyl galactoseamine (GalNAc).
- the targeting moiety comprises 3 ligands.
- the targeting moiety of the invention comprises 3 N-acetyl galactoseamine ligands.
- GalNac or Gal-NAc refers to 2-(Acetylamino)-2-deoxy-D-galactopyranose, commonly referred to in the literature as N-acetyl galactosamine.
- N-acetyl galactosamine refers to 2-(Acetylamino)-2-deoxy-D-galactopyranose.
- GalNac or Gal-NAc of the present invention refers to 2-(Acetylamino)-2-deoxy-D-galactopyranose, which is in the ⁇ -form: 2-(Acetylamino)-2-deoxy- ⁇ -D-galactopyranose.
- 2-(Acetylamino)-2-deoxy-D-galactopyranose which is depicted for reference below.
- 2-(Acetylamino)-2-deoxy-D-galactopyranose 2-(Acetylamino)-2-deoxy- ⁇ -D-galactopyranose
- 2-(Acetylamino)-2-deoxy- ⁇ -D-galactopyranose 2-(Acetylamino)-2-deoxy- ⁇ -D-galactopyranose
- conjugate groups comprise the structural features above that are consistent with the appended claims.
- conjugate groups have the following structure:
- conjugate groups have the following structure:
- the conjugates are bound to a nucleoside of the antisense oligonucleotide at the 2', 3', of 5' position of the nucleoside.
- the conjugated antisense compound can have the following structure: wherein
- a conjugated antisense compound has the following structure: wherein
- the conjugate linker comprises at least one cleavable bond.
- the conjugated antisense compound has the following structure:
- conjugated antisense compounds comprise an RNase H based oligonucleotide (such as a gapmer) or a splice modulating oligonucleotide (such as a fully modified oligonucleotide) and any conjugate group comprising at least one, two, or three GalNAc groups.
- a conjugated antisense compound comprises any conjugate group found in any of the following references: Lee, Carbohydr Res, 1978, 67, 509-514 ; Connolly et al., J Biol Chem, 1982, 257, 939-945 ; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548 ; Lee et al., Biochem, 1984, 23, 4255-4261 ; Lee et al., Glycoconjugate J, 1987, 4, 317-328 ; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676 ; Biessen et al., J Med Chem, 1995, 38, 1538-1546 ; Valentijn et al., Tetrahedron, 1997, 53, 759-770 ; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490 ; Lee et al., Bioconjug Chem, 1997
- conjugated antisense compounds exhibit potent target RNA reduction in vivo.
- unconjugated antisense compounds accumulate in the kidney.
- conjugated antisense compounds accumulate in the liver.
- conjugated antisense compounds are well tolerated. Such properties render conjugated antisense compounds particularly useful for inhibition of many target RNAs, including, but not limited to those involved in metabolic, cardiovascular and other diseases, disorders or conditions.
- methods of treating such diseases, disorders or conditions by contacting liver tissues with the conjugated antisense compounds targeted to RNAs associated with such diseases, disorders or conditions.
- conjugated antisense compounds are more potent than unconjugated counterpart at a particular tissue concentration.
- the conjugate may allow the conjugated antisense compound to enter the cell more efficiently or to enter the cell more productively.
- conjugated antisense compounds may exhibit greater target reduction as compared to its unconjugated counterpart wherein both the conjugated antisense compound and its unconjugated counterpart are present in the tissue at the same concentrations.
- conjugated antisense compounds may exhibit greater target reduction as compared to its unconjugated counterpart wherein both the conjugated antisense compound and its unconjugated counterpart are present in the liver at the same concentrations.
- the conjugate groups described herein may further improve potency by increasing the affinity of the conjugated antisense compound for a particular type of cell or tissue. In certain embodiments, the conjugate groups described herein may further improve potency by increasing recognition of the conjugated antisense compound by one or more cell-surface receptors.. In certain embodiments, the conjugate groups described herein may further improve potency by facilitating endocytosis of the conjugated antisense compound.
- the cleavable moiety may further improve potency by allowing the conjugate to be cleaved from the antisense oligonucleotide after the conjugated antisense compound has entered the cell. Accordingly, in certain embodiments, conjugated antisense compounds can be administered at doses lower than would be necessary for unconjugated antisense oligonucleotides.
- Phosphorothioate linkages have been incorporated into antisense oligonucleotides previously. Such phosphorothioate linkages are resistant to nucleases and so improve stability of the oligonucleotide. Further, phosphorothioate linkages also bind certain proteins, which results in accumulation of antisense oligonucleotide in the liver. Oligonucleotides with fewer phosphorothioate linkages accumulate less in the liver and more in the kidney (see, for example, Geary, R., "Pharmacokinetic Properties of 2'-O-(2-Methoxyethyl)-Modified Oligonucleotide Analogs in Rats," Journal of Pharmacology and Experimental Therapeutics, Vol.
- oligonucleotides with fewer phosphorothioate internucleoside linkages and more phosphodiester internucleoside linkages accumulate less in the liver and more in the kidney.
- this is undesirable for several reasons (1) less drug is getting to the site of desired action (liver); (2) drug is escaping into the urine; and (3) the kidney is exposed to relatively high concentration of drug which can result in toxicities in the kidney.
- phosphorothioate linkages provide important benefits.
- administration of oligonucleotides uniformly linked by phosphorothioate internucleoside linkages induces one or more proinflammatory reactions.
- administration of oligonucleotides wherein most of the internucleoside linkages comprise phosphorothioate internucleoside linkages induces one or more proinflammatory reactions.
- the degree of proinflammatory effect may depend on several variables (e.g. backbone modification, off-target effects, nucleobase modifications, and/or nucleoside modifications) see for example: Toxicologic Properties in Antisense a Drug Technology, Chapter 12, pages 342-351, Crooke, S.T., ed., 2008 ).
- the degree of proinflammatory effect may be mitigated by adjusting one or more variables. For example the degree of proinflammatory effect of a given oligonucleotide may be mitigated by replacing any number of phosphorothioate internucleoside linkages with phosphodiester internucleoside linkages and thereby reducing the total number of phosphorothioate internucleoside linkages.
- the number of phosphorothioate linkages may be reduced by replacing phosphorothioate linkages with phosphodiester linkages.
- the antisense compound having fewer phosphorothioate linkages and more phosphodiester linkages may induce less proinflammatory reactions or no proinflammatory reaction.
- the antisense compound having fewer phosphorothioate linkages and more phosphodiester linkages may induce fewer proinflammatory reactions
- the antisense compound having fewer phosphorothioate linkages and more phosphodiester linkages may not accumulate in the liver and may be less efficacious at the same or similar dose as compared to an antisense compound having more phosphorothioate linkages.
- conjugated antisense compounds accumulate more in the liver and less in the kidney than unconjugated counterparts, even when some of the phosphorothioate linkages are replaced with less proinflammatory phosphodiester internucleoside linkages. In certain embodiments, conjugated antisense compounds accumulate more in the liver and are not excreted as much in the urine compared to its unconjugated counterparts, even when some of the phosphorothioate linkages are replaced with less proinflammatory phosphodiester internucleoside linkages. In certain embodiments, the use of a conjugate allows one to design more potent and better tolerated antisense drugs. Indeed, in certain embodiments, conjugated antisense compounds have larger therapeutic indexes than unconjugated counterparts.
- conjugated antisense compound to be administered at a higher absolute dose, because there is less risk of proinflammatory response and less risk of kidney toxicity.
- This higher dose allows one to dose less frequently, since the clearance (metabolism) is expected to be similar.
- the compound is more potent, as described above, one can allow the concentration to go lower before the next dose without losing therapeutic activity, allowing for even longer periods between dosing.
- the inclusion of some phosphorothioate linkages remains desirable.
- the terminal linkages are vulnerable to exonucleases and so in certain embodiments, those linkages are phosphorothioate or other modified linkage.
- Internucleoside linkages linking two deoxynucleosides are vulnerable to endonucleases and so in certain embodiments those linkages are phosphorothioate or other modified linkage.
- Internucleoside linkages between a modified nucleoside and a deoxynucleoside where the deoxynucleoside is on the 5' side of the linkage deoxynucleosides are vulnerable to endonucleases and so in certain embodiments those linkages are phosphorothioate or other modified linkage.
- Internucleoside linkages between two modified nucleosides of certain types and between a deoxynucleoside and a modified nucleoside of certain type where the modified nucleoside is at the 5' side of the linkage are sufficiently resistant to nuclease digestion, that the linkage can be phosphodiester.
- the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 16 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 15 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 14 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 13 phosphorothioate linkages.
- the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 12 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 11 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 10 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 9 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of a conjugated antisense compound comprises fewer than 8 phosphorothioate linkages.
- antisense compounds comprising one or more conjugate group described herein has increased activity and/or potency and/or tolerability compared to a parent antisense compound lacking such one or more conjugate group. Accordingly, in certain embodiments, attachment of such conjugate groups to an oligonucleotide is desirable. Such conjugate groups may be attached at the 5'-, and/or 3'- end of an oligonucleotide. In certain instances, attachment at the 5'-end is synthetically desirable. Typically, oligonucleotides are synthesized by attachment of the 3' terminal nucleoside to a solid support and sequential coupling of nucleosides from 3' to 5' using techniques that are well known in the art.
- a conjugate group is desired at the 3'-terminus, one may (1) attach the conjugate group to the 3'-terminal nucleoside and attach that conjugated nucleoside to the solid support for subsequent preparation of the oligonucleotide or (2) attach the conjugate group to the 3'-terminal nucleoside of a completed oligonucleotide after synthesis.
- attaching a conjugate group to the 5'-terminal nucleoside is synthetically easier than attachment at the 3'-end.
- certain conjugate groups have synthetic advantages. For Example, certain conjugate groups comprising phosphorus linkage groups are synthetically simpler and more efficiently prepared than other conjugate groups, including conjugate groups reported previously (e.g., WO/2012/037254 ).
- conjugated antisense compounds are administered to a subject.
- antisense compounds comprising one or more conjugate group described herein has increased activity and/or potency and/or tolerability compared to a parent antisense compound lacking such one or more conjugate group.
- the conjugate group helps with distribution, delivery, and/or uptake into a target cell or tissue.
- Example 20 a conjugated oligonucleotide was administered to mice and a number of different chemical species, each comprising a different portion of the conjugate group remaining on the oligonucleotide, were detected (Table 23a).
- This conjugated antisense compound demonstrated good potency (Table 23).
- such metabolite profile of multiple partial cleavage of the conjugate group does not interfere with activity/potency.
- a prodrug conjuggated oligonucleotide
- conjugate groups at the 5'-end are more likely to result in complete metabolism of the conjugate group. Without being bound by mechanism it may be that endogenous enzymes responsible for metabolism at the 5' end (e.g., 5' nucleases) are more active/efficient than the 3' counterparts.
- the specific conjugate groups are more amenable to metabolism to a single active species. In certain embodiments, certain conjugate groups are more amenable to metabolism to the oligonucleotide.
- oligomeric compounds of the present invention are antisense compounds.
- the oligomeric compound is complementary to a target nucleic acid.
- a target nucleic acid is an RNA.
- a target nucleic acid is a non-coding RNA.
- a target nucleic acid encodes a protein.
- a target nucleic acid is selected from a mRNA, a pre-mRNA, a microRNA, a non-coding RNA, including small non-coding RNA, and a promoter-directed RNA.
- oligomeric compounds are at least partially complementary to more than one target nucleic acid.
- oligomeric compounds of the present invention may be microRNA mimics, which typically bind to multiple targets.
- antisense compounds comprise a portion having a nucleobase sequence at least 70% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, antisense compounds comprise a portion having a nucleobase sequence at least 80% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, antisense compounds comprise a portion having a nucleobase sequence at least 90% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, antisense compounds comprise a portion having a nucleobase sequence at least 95% complementary to the nucleobase sequence of a target nucleic acid.
- antisense compounds comprise a portion having a nucleobase sequence at least 98% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, antisense compounds comprise a portion having a nucleobase sequence that is 100% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, antisense compounds are at least 70%, 80%, 90%, 95%, 98%, or 100% complementary to the nucleobase sequence of a target nucleic acid over the entire length of the antisense compound.
- Antisense mechanisms include any mechanism involving the hybridization of an oligomeric compound with target nucleic acid, wherein the hybridization results in a biological effect.
- hybridization results in either target nucleic acid degradation or occupancy with concomitant inhibition or stimulation of the cellular machinery involving, for example, translation, transcription, or polyadenylation of the target nucleic acid or of a nucleic acid with which the target nucleic acid may otherwise interact.
- RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are "DNA-like" elicit RNase H activity in mammalian cells. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of DNA-like oligonucleotide-mediated inhibition of gene expression.
- Antisense mechanisms also include, without limitation RNAi mechanisms, which utilize the RISC pathway.
- RNAi mechanisms include, without limitation siRNA, ssRNA and microRNA mechanisms.
- Such mechanisms include creation of a microRNA mimic and/or an anti-microRNA.
- Antisense mechanisms also include, without limitation, mechanisms that hybridize or mimic non-coding RNA other than microRNA or mRNA.
- non-coding RNA includes, but is not limited to promoter-directed RNA and short and long RNA that effects transcription or translation of one or more nucleic acids.
- oligonucleotides comprising conjugates described herein are RNAi compounds. In certain embodiments, oligomeric oligonucleotides comprising conjugates described herein are ssRNA compounds. In certain embodiments, oligonucleotides comprising conjugates described herein are paired with a second oligomeric compound to form an siRNA. In certain such embodiments, the second oligomeric compound also comprises a conjugate. In certain embodiments, the second oligomeric compound is any modified or unmodified nucleic acid. In certain embodiments, the oligonucleotides comprising conjugates described herein is the antisense strand in an siRNA compound.
- the oligonucleotides comprising conjugates described herein is the sense strand in an siRNA compound.
- the conjugate may be on the sense strand, the antisense strand or both the sense strand and the antisense strand.
- conjugated antisense compounds target any nucleic acid.
- the target nucleic acid encodes a target protein that is clinically relevant. In such embodiments, modulation of the target nucleic acid results in clinical benefit.
- Certain target nucleic acids include, but are not limited to, the target nucleic acids illustrated in Table 1.
- Table 1 Certain Target Nucleic Acids Target Species GENBANK® Accession Number SEQ ID NO Androgen Receptor (AR) Human NT_011669.17 truncated from nucleobases 5079000 to 5270000 1 Apolipoprotein (a) (Apo(a)) Human NM_005577.2 2 Apolipoprotein B (ApoB) Human NM_000384.1 3 Apolipoprotein C-III (ApoCIII) Human NT_033899.8 truncated from nucleobases 20262640 to 20266603 4 Apolipoprotein C-III (ApoCIII) Human NM_000040.1 5 C-Reactive Protein (CRP) Human M11725.1 6 eIF4E Human M15353.1 7 Factor VII Human NT_027140.6 truncated from nucleobases 1255000 to 1273000 8 Factor XI Human NM_000128.3 9 Glucocorticoid Re
- the targeting process usually includes determination of at least one target region, segment, or site within the target nucleic acid for the antisense interaction to occur such that the desired effect will result.
- a target region is a structurally defined region of the nucleic acid.
- a target region may encompass a 3' UTR, a 5' UTR, an exon, an intron, a coding region, a translation initiation region, translation termination region, or other defined nucleic acid region or target segment.
- a target segment is at least about an 8-nucleobase portion of a target region to which a conjugated antisense compound is targeted.
- Target segments can include DNA or RNA sequences that comprise at least 8 consecutive nucleobases from the 5'-terminus of one of the target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5'-terminus of the target segment and continuing until the DNA or RNA comprises about 8 to about 30 nucleobases).
- Target segments are also represented by DNA or RNA sequences that comprise at least 8 consecutive nucleobases from the 3'-terminus of one of the target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3'-terminus of the target segment and continuing until the DNA or RNA comprises about 8 to about 30 nucleobases).
- Target segments can also be represented by DNA or RNA sequences that comprise at least 8 consecutive nucleobases from an internal portion of the sequence of a target segment, and may extend in either or both directions until the conjugated antisense compound comprises about 8 to about 30 nucleobases.
- antisense compounds targeted to the nucleic acids listed in Table 1 can be modified as described herein.
- the antisense compounds can have a modified sugar moiety, an unmodified sugar moiety or a mixture of modified and unmodified sugar moieties as described herein.
- the antisense compounds can have a modified internucleoside linkage, an unmodified internucleoside linkage or a mixture of modified and unmodified internucleoside linkages as described herein.
- the antisense compounds can have a modified nucleobase, an unmodified nucleobase or a mixture of modified and unmodified nucleobases as described herein.
- the antisense compounds can have a motif as described herein.
- antisense compounds targeted to the nucleic acids listed in Table 1 can be conjugated as described herein.
- AR is a transcription factor implicated as a driver of prostate cancer. AR is activated by binding to its hormone ligands: androgen, testosterone, and/or DHT. Androgen deprivation therapy, also known as "chemical castration," is a first-line treatment strategy against hormone-sensitive, androgen-dependent prostate cancer that reduces circulating androgen levels and thereby inhibits AR activity.
- Androgen deprivation therapy frequently leads to the emergence and growth of "castration-resistant" advanced prostate cancer, in which AR signaling is reactivated independent of ligand binding. The mechanisms underlying castration resistance in advanced prostate cancer remain unclear.
- conjugated antisense compounds are targeted to an AR nucleic acid having the sequence of GENBANK® Accession No. NT_011669.17 nucleobases 5079000 to 5270000, incorporated herein as SEQ ID NO: 1.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1.
- a conjugated antisense compound targeted to SEQ ID NO: 1 comprises an at least 8 consecutive nucleobase sequence selected from the nucleobase sequence of any of SEQ ID NOs: 17-24. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 1 comprises a nucleobase sequence selected from the nucleobase sequence of any of SEQ ID NOs: 17-24. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to an AR nucleic acid for modulating the expression of AR in a subject. In certain embodiments, the expression of AR is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to an AR nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has prostate cancer, such as castration-resistant prostate cancer.
- the subject has prostate cancer resistant to a diarylhydantoin Androgen Receptor (AR) inhibitor, such as MDV3100, which is also known as Enzalutamide.
- MDV3100 or Enzalutamide is an experimental androgen receptor antagonist drug developed by Medivation for the treatment of castration-resistant prostate cancer.
- the subject has breast cancer.
- the subject's breast cancer can have one or more of the following characteristics: Androgen Receptor positive, dependent on androgen for growth, Estrogen Receptor (ER) negative, independent of estrogen for growth, Progesterone Receptor (PR) negative, independent of progesterone for growth, or Her2/neu negative.
- the breast cancer or breast cancer cell is apocrine.
- the invention provides methods for using a conjugated antisense compound targeted to an AR nucleic acid in the preparation of a medicament.
- Apolipoprotein (a) (Apo(a))
- Apo(a) protein is linked via a disulfide bond to a single ApoB protein to form a lipoprotein(a) (Lp(a)) particle.
- the Apo(a) protein shares a high degree of homology with plasminogen particularly within the kringle IV type 2 repetitive domain. It is thought that the kringle repeat domain in Apo(a) may be responsible for its pro-thrombotic and anti-fibrinolytic properties, potentially enhancing atherosclerotic progression.
- Apo(a) is transcriptionally regulated by IL-6 and in studies in rheumatoid arthritis patients treated with an IL-6 inhibitor (tocilizumab), plasma levels were reduced by 30% after 3 month treatment.
- Lp(a) has been shown to preferentially bind oxidized phospholipids and potentiate vascular inflammation. Further, studies suggest that the Lp(a) particle may also stimulate endothelial permeability, induce plasminogen activator inhibitor type-1 expression and activate macrophage interleukin-8 secretion. Importantly, recent genetic association studies revealed that Lp(a) was an independent risk factor for myocardial infarction, stroke, peripheral vascular disease and abdominal aortic aneurysm. Further, in the Precocious Coronary Artery Disease (PROCARDIS) study, Clarke et al. described robust and independent associations between coronary heart disease and plasma Lp(a) concentrations.
- PROCARDIS Precocious Coronary Artery Disease
- conjugated antisense compounds are targeted to an Apo(a) nucleic acid having the sequence of GENBANK® Accession No. NM_005577.2, incorporated herein as SEQ ID NO: 2.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 2.
- a conjugated antisense compound targeted to SEQ ID NO: 2 comprises an at least 8 consecutive nucleobase sequence selected from the nucleobase sequence of any of SEQ ID NOs: 25-30. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 2 comprises a nucleobase sequence selected from the nucleobase sequence of any of SEQ ID NOs: 25-30. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to an Apo(a) nucleic acid for modulating the expression of Apo(a) in a subject. In certain embodiments, the expression of Apo(a) is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to an Apo(a) nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a cardiovascular and/or metabolic disease, disorder or condition.
- the subject has hypercholesterolemia, non-familial hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, and/or non-alcoholic fatty liver disease.
- the invention provides methods for using a conjugated antisense compound targeted to an Apo(a) nucleic acid in the preparation of a medicament.
- Apolipoprotein B (ApoB)
- ApoB also known as apolipoprotein B-100; ApoB-100, apolipoprotein B-48; ApoB-48 and Ag(x) antigen
- ApoB performs a variety of activities, from the absorption and processing of dietary lipids to the regulation of circulating lipoprotein levels ( Davidson and Shelness, Annu. Rev. Nutr., 2000, 20, 169-193 ).
- ApoB-100 is the major protein component of LDL-C and contains the domain required for interaction of this lipoprotein species with the LDL receptor. Elevated levels of LDL-C are a risk factor for cardiovascular disease, including atherosclerosis.
- Antisense compounds targeting ApoB have been previously disclosed in WO2004/044181 .
- An antisense oligonucleotide targeting ApoB, KYNAMROTM, has been approved by the U.S.
- FDA Food and Drug Administration
- LDL-C low density lipoprotein-cholesterol
- ApoB ApoB
- TC total cholesterol
- non HDL-C non-high density lipoprotein-cholesterol
- HoFH homozygous familial hypercholesterolemia
- conjugated antisense compounds are targeted to an ApoB nucleic acid having the sequence of GENBANK® Accession No. NM_000384.1, incorporated herein as SEQ ID NO: 3.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 3.
- a conjugated antisense compound targeted to SEQ ID NO: 3 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 31. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 3 comprises a nucleobase sequence of SEQ ID NO: 31. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoB nucleic acid for modulating the expression of ApoB in a subject. In certain embodiments, the expression of ApoB is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoB nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a cardiovascular and/or metabolic disease, disorder or condition.
- the subject has hypercholesterolemia, non-familial hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, and/or non-alcoholic fatty liver disease.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoB nucleic acid in the preparation of a medicament.
- ApoCIII is a constituent of HDL and of triglyceride (TG)-rich lipoproteins. Elevated ApoCIII levels are associated with elevated TG levels and diseases such as cardiovascular disease, metabolic syndrome, obesity and diabetes. Elevated TG levels are associated with pancreatitis. ApoCIII slows clearance of TG-rich lipoproteins by inhibiting lipolysis through inhibition of lipoprotein lipase (LPL) and through interfering with lipoprotein binding to cell-surface glycosaminoglycan matrix. Antisense compounds targeting ApoCIII have been previously disclosed in WO2004/093783 and WO2012/149495 .
- an antisense oligonucleotide targeting ApoCIII is in Phase II clinical trials to assess its effectiveness in the treatment of diabetes or hypertriglyceridemia.
- ISIS-APOCIII Rx is in Phase II clinical trials to assess its effectiveness in the treatment of diabetes or hypertriglyceridemia.
- conjugated antisense compounds are targeted to an ApoCIII nucleic acid having the sequence of GENBANK® Accession No. NT_033899.8 truncated from nucleobases 20262640 to 20266603, incorporated herein as SEQ ID NO: 4.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 4.
- conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands.
- such antisense compounds comprise a conjugate disclosed herein.
- conjugated antisense compounds are targeted to an ApoCIII nucleic acid having the sequence of GENBANK® Accession No. NM_000040.1, incorporated herein as SEQ ID NO: 5.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 5.
- conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands.
- antisense compounds comprise a conjugate disclosed herein.
- a conjugated antisense compound targeted to SEQ ID NO: 5 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 32. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 5 comprises a nucleobase sequence of SEQ ID NO: 32. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoCIII nucleic acid for modulating the expression of ApoCIII in a subject. In certain embodiments, the expression of ApoCIII is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoCIII nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a cardiovascular and/or metabolic disease, disorder or condition.
- the subject has hypertriglyceridemia, non-familial hypertriglyceridemia, familial hypertriglyceridemia, heterozygous familial hypertriglyceridemia, homozygous familial hypertriglyceridemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, pancreatitis and/or non-alcoholic fatty liver disease.
- the invention provides methods for using a conjugated antisense compound targeted to an ApoCIII nucleic acid in the preparation of a medicament.
- CRP C-Reactive Protein
- CRP also known as PTX1
- PTX1 is an essential human acute-phase reactant produced in the liver in response to a variety of inflammatory cytokines.
- the protein first identified in 1930, is highly conserved and considered to be an early indicator of infectious or inflammatory conditions.
- Plasma CRP levels increase 1,000-fold in response to infection, ischemia, trauma, burns, and inflammatory conditions.
- lipid-lowering therapy such as statin therapy
- antisense compounds targeting CRP have been previously disclosed in WO2003/010284 and WO2005/005599 .
- An antisense oligonucleotide targeting CRP, ISIS-CRP Rx is currently in Phase 2 clinical trials to study its effectiveness in treating subjects with rheumatoid arthritis and paroxysmal atrial fibrillation.
- ISIS-CRP Rx An antisense oligonucleotide targeting CRP, ISIS-CRP Rx .
- conjugated antisense compounds are targeted to a CRP nucleic acid having the sequence of GENBANK® Accession No. M11725.1, incorporated herein as SEQ ID NO: 6.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 6.
- a conjugated antisense compound targeted to SEQ ID NO: 6 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 33. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 6 comprises a nucleobase sequence of SEQ ID NO: 33. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a CRP nucleic acid for modulating the expression of CRP in a subject. In certain embodiments, the expression of CRP is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a CRP nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a cardiovascular and/or metabolic disease, disorder or condition.
- the subject has hypercholesterolemia, non-familial hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease.
- the individual has paroxysmal atrial fibrillation, acute coronary syndrome, vascular injury, arterial occlusion, unstable angina, post peripheral vascular disease, post myocardial infarction (MI), thrombosis, deep vein thrombus, end-stage renal disease (ESRD), chronic renal failure, complement activation, congestive heart failure, or systemic vasculitis.
- the individual has had a stroke.
- the individual has undergone a procedure selected from elective stent placement, angioplasty, post percutaneous transluminal angioplasty (PTCA), cardiac transplantation, renal dialysis or cardiopulmonary bypass.
- the individual has an inflammatory disease.
- the inflammatory disease is selected from inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, or osteoarthritis.
- the invention provides methods for using a conjugated antisense compound targeted to a CRP nucleic acid in the preparation of a medicament.
- eIF4E Overexpression of eIF4E has been reported in many human cancers and cancer-derived cell lines and also leads to oncogenic transformation of cells and invasive/metastatic phenotype in animal models. Unlike non-transformed, cultured cells, transformed cell lines express eIF4E independently of the presence of serum growth factors ( Rosenwald, Cancer Lett., 1995, 98, 77-82 ). Excess eIF4E leads to aberrant growth and neoplastic morphology in HeLa cells and also causes tumorigenic transformation in NIH 3T3 and Rat2 fibroblasts, as judged by anchorage-independent growth, formation of transformed foci in culture and tumor formation in nude mice ( De Benedetti et al., Proc. Natl. Acad. Sci. U S A, 1990, 87, 8212-8216 ; and Lazaris-Karatzas et al., Nature, 1990, 345, 544-547 ).
- eIF4E is found elevated in several human cancers, including but not limited to non-Hodgkin's lymphomas, colon adenomas and carcinomas and larynx, head and neck, prostate, breast and bladder cancers ( Crew et al., Br. J. Cancer, 2000, 82, 161-166 ; Graff et al., Clin. Exp. Metastasis, 2003, 20, 265-273 ; Haydon et al., Cancer, 2000, 88, 2803-2810 ; Kerekatte et al., Int. J. Cancer, 1995, 64, 27-31 ; Rosenwald et al., Oncogene, 1999, 18, 2507-2517 ; Wang et al., Am. J.
- conjugated antisense compounds are targeted to an eIF4E nucleic acid having the sequence of GENBANK® Accession No. M15353.1, incorporated herein as SEQ ID NO: 7.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 7.
- a conjugated antisense compound targeted to SEQ ID NO: 7 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 34. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 7 comprises a nucleobase sequence of SEQ ID NO: 34. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to an eIF4E nucleic acid for modulating the expression of eIF4E in a subject. In certain embodiments, the expression of eIF4E is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to an eIF4E nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has cancer.
- the cancer is prostate cancer.
- the invention provides methods for using a conjugated antisense compound targeted to an eIF4E nucleic acid in the preparation of a medicament.
- Coagulation Factor VII (also known as serum prothrombin conversion accelerator) is a key component of the tissue factor coagulation pathway. Clinicians have linked elevated levels of Factor VII activity with poor prognosis in several thrombotic diseases, such as heart attacks, and with cancer-associated thrombosis, which is the second leading cause of death in cancer patients. In preclinical studies, antisense inhibition of Factor VII rapidly reduced Factor VII activity by more than 90 percent in three days with no observed increase in bleeding, which is a common side effect of currently available anti-thrombotic drugs. Antisense compounds targeting Factor VII have been previously disclosed in WO2009/061851 , WO2012/174154 , and PCT Application no. PCT/US2013/025381
- conjugated antisense compounds are targeted to a Factor VII nucleic acid having the sequence of GENBANK® Accession No. NT_027140.6 truncated from nucleobases 1255000 to 1273000), incorporated herein as SEQ ID NO: 8.
- a conjugated antisense compound targeted to SEQ ID NO: 8 is at least 90%, at least 95% or 100% complementary to SEQ ID NO: 8.
- a conjugated antisense compound targeted to SEQ ID NO: 8 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 35-43. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 8 comprises a nucleobase sequence of SEQ ID NOs: 35-43. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a Factor VII nucleic acid for modulating the expression of Factor VII in a subject. In certain embodiments, the expression of Factor VII is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a Factor VII nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has or is at risk of developing a thromboembolic condition, such as, heart attack, stroke, deep vein thrombosis, or pulmonary embolism.
- the subject is at risk of developing a thromboemoblic condition and/or otherwise in need of anticoagulant therapy. Examples of such subjects include those undergoing major orthopedic surgery and patients in need of chronic anticoagulant treatment.
- the subject has or is at risk of developing an inflammatory disease, disorder or condition.
- the subject has or is at risk of developing allergic diseases (e.g., allergic rhinitis, chronic rhinosinusitis), autimmune diseases (e.g, multiple sclerosis, arthritis, scleroderma, psoriasis, celiac disease), cardiovascular diseases, colitis, diabetes (e.g., type 1 insulin-dependent diabetes mellitus), hypersensitivities (e.g., Type1, 2, 3 or 4 hypersensitivity), infectious diseases (e.g., viral infection, mycobacterial infection, helminth infection), posterior uveitis, airway hyperresponsiveness, asthma, atopic dermatitis, colitis, endometriosis, thyroid disease (e.g., Graves' disease) and pancreatitis.
- allergic diseases e.g., allergic rhinitis, chronic rhinosinusitis
- autimmune diseases e.g, multiple sclerosis, arthritis, scleroderma, psoriasis, celiac
- the invention provides methods for using a conjugated antisense compound targeted to a Factor VII nucleic acid in the preparation of a medicament.
- Coagulation factor XI (also known as plasma thromboplastin antecedent) is an important member of the coagulation pathway.
- High levels of Factor XI increase the risk of thrombosis, a process involving aberrant blood clot formation responsible for most heart attacks and strokes. Elevated levels of Factor XI also increase the risk of venous thrombosis, a common problem after surgery, particularly major orthopedic procedures, such as knee or hip replacement. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk.
- Antisense compounds targeting Factor XI have been previously disclosed in WO2010/045509 and WO2010/121074 .
- ISIS-FXI Rx an antisense oligonucleotide targeting Factor XI
- conjugated antisense compounds are targeted to a Factor XI nucleic acid having the sequence of GENBANK® Accession No. NM_000128.3, incorporated herein as SEQ ID NO: 9.
- a conjugated antisense compound is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 9.
- a conjugated antisense compound targeted to SEQ ID NO: 9 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 44-48. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 9 comprises a nucleobase sequence of SEQ ID NOs: 44-48. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a Factor XI nucleic acid for modulating the expression of Factor XI in a subject. In certain embodiments, the expression of Factor XI is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a Factor XI nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has or is at risk of developing a thromboembolic condition, such as, heart attack, stroke, deep vein thrombosis, or pulmonary embolism.
- the subject is at risk of developing a thromboemoblic condition and/or otherwise in need of anticoagulant therapy. Examples of such subjects include those undergoing major orthopedic surgery and patients in need of chronic anticoagulant treatment.
- the subject has or is at risk of developing an inflammatory disease, disorder or condition.
- the subject has or is at risk of developing allergic diseases (e.g., allergic rhinitis, chronic rhinosinusitis), autimmune diseases (e.g, multiple sclerosis, arthritis, scleroderma, psoriasis, celiac disease), cardiovascular diseases, colitis, diabetes (e.g., type 1 insulin-dependent diabetes mellitus), hypersensitivities (e.g., Type1, 2, 3 or 4 hypersensitivity), infectious diseases (e.g., viral infection, mycobacterial infection, helminth infection), posterior uveitis, airway hyperresponsiveness, asthma, atopic dermatitis, colitis, endometriosis, thyroid disease (e.g., Graves' disease) and pancreatitis.
- allergic diseases e.g., allergic rhinitis, chronic rhinosinusitis
- autimmune diseases e.g, multiple sclerosis, arthritis, scleroderma, psoriasis, celiac
- the invention provides methods for using a conjugated antisense compound targeted to a Factor XI nucleic acid in the preparation of a medicament.
- GCCR Glucocorticoid Receptor
- glucocorticoid receptor also known as nuclear receptor subfamily 3, group C, member 1; NR3C1; GCCR; GCR; GRL; Glucocorticoid receptor, lymphocyte
- the gene is located on human chromosome 5q11-q13 and consists of 9 exons ( Encio and Detera-Wadleigh, J Biol Chem, 1991, 266, 7182-7188 ; Gehring et al., Proc Natl Acad Sci USA, 1985, 82, 3751-3755 ).
- the human glucocorticoid receptor is comprised of three major domains, the N-terminal activation domain, the central DNA-binding domain and the C-terminal ligand-binding domain ( Giguere et al., Cell, 1986, 46, 645-652 ). In the absence of ligand, the glucocorticoid receptor forms a large heteromeric complex with several other proteins, from which it dissociates upon ligand binding.
- glucocorticoid agonists increase hepatic glucose production by activating the glucocorticoid receptor, which subsequently leads to increased expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase.
- PPCK phosphoenolpyruvate carboxykinase
- glucose-6-phosphatase Through gluconeogenesis, glucose is formed through non-hexose precursors, such as lactate, pyruvate and alanine ( Link, Curr Opin Investig Drugs, 2003, 4, 421-429 ).
- Antisense compounds targeting GCCR have been previously disclosed in WO2007/035759 , WO2005/071080 , and PCT application no. PCT/US2012/061984 .
- An antisense oligonucleotide targeting GCCR, ISIS-GCCR Rx recently completed a Phase I clinical study with positive results.
- conjugated antisense compounds are targeted to a GCCR nucleic acid having the sequence of the complement of GENBANK Accession No. NT_029289.10 truncated from nucleobases 3818000 to 3980000, incorporated herein as SEQ ID NO: 10.
- a conjugated antisense compound targeted to SEQ ID NO: 10 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 10.
- a conjugated antisense compound targeted to SEQ ID NO: 10 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 49-59. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 10 comprises a nucleobase sequence of SEQ ID NOs: 49-59. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a GCCR nucleic acid for modulating the expression of GCCR in a subject. In certain embodiments, the expression of GCCR is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a GCCR nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has metabolic related diseases, including metabolic syndrome, diabetes mellitus, insulin resistance, diabetic dyslipidemia, hypertriglyceridemia, obesity and weight gain.
- Diabetes mellitus is characterized by numerous physical and physiological symptoms. Any symptom known to one of skill in the art to be associated with Type 2 diabetes can be ameliorated or otherwise modulated as set forth above in the methods described above.
- the symptom is a physical symptom selected from the group consisting of increased glucose levels, increased weight gain, frequent urination, unusual thirst, extreme hunger, extreme fatigue, blurred vision, frequent infections, tingling or numbness at the extremities, dry and itchy skin, weight loss, slow-healing sores, and swollen gums.
- the symptom is a physiological symptom selected from the group consisting of increased insulin resistance, increased glucose levels, increased fat mass, decreased metabolic rate, decreased glucose clearance, decreased glucose tolerance, decreased insulin sensitivity, decreased hepatic insulin sensitivity, increased adipose tissue size and weight, increased body fat, and increased body weight.
- the invention provides methods for using a conjugated antisense compound targeted to a GCCR nucleic acid in the preparation of a medicament.
- Glucagon Receptor GCGR
- Diabetes is a chronic metabolic disorder characterized by impaired insulin secretion and/or action.
- type 2 diabetes T2DM
- insulin resistance leads to an inability of insulin to control the activity of gluconeogenic enzymes, and many subjects also exhibit inappropriate levels of circulating glucagon in the fasting and postprandial state.
- Glucagon is secreted from the ⁇ -cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production ( Quesada et al., J. Endocrinol. 2008. 199: 5-19 ).
- Glucagon exerts its action on target tissues via the activation of its receptor, GCGR.
- the glucagon receptor is a 62 kDa protein that is a member of the class B G-protein coupled family of receptors ( Brubaker et al., Recept. Channels. 2002. 8: 179-88 ).
- GCGR activation leads to signal transduction by G proteins (G s ⁇ and G q ), whereby G s ⁇ activates adenylate cyclase, which causes cAMP production, resulting in an increase in levels of protein kinase A.
- G proteins G proteins
- G s ⁇ activates adenylate cyclase, which causes cAMP production, resulting in an increase in levels of protein kinase A.
- GCGR signaling in the liver results in increased hepatic glucose production by induction of glycogenolysis and gluconeogenesis along with inhibition of glycogenesis ( Jiang and Zhang. Am. J. Physiol. Endocrinol. Metab. 2003.
- GCGR is also expressed in extrahepatic tissues, which includes heart, intestinal smooth muscle, kidney, brain, and adipose tissue ( Hansen et al., Peptides. 1995. 16: 1163-1166 ).
- Antisense compounds targeting GCGR have been previously disclosed in WO2004/096996 , WO2004/096016 , WO2007/035771 , and WO2013/043817 .
- An antisense oligonucleotide targeting GCGR, ISIS-GCGR Rx recently completed a Phase I clinical study with positive results. However, there is still a need to provide patients with additional and more potent treatment options.
- conjugated antisense compounds are targeted to a GCGR nucleic acid having the sequence of GENBANK® Accession No NW_926918.1 truncated from nucleobases 16865000 to 16885000, incorporated herein as SEQ ID NO: 11.
- a conjugated antisense compound targeted to SEQ ID NO: 11 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 11.
- a conjugated antisense compound targeted to SEQ ID NO: 11 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 60-67. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 11 comprises a nucleobase sequence of SEQ ID NOs: 60-67. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a GCGR nucleic acid for modulating the expression of GCGR in a subject. In certain embodiments, the expression of GCGR is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a GCGR nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has metabolic related diseases, including metabolic syndrome, diabetes mellitus, insulin resistance, diabetic dyslipidemia, hypertriglyceridemia, obesity and weight gain.
- Diabetes mellitus is characterized by numerous physical and physiological signs and/or symptoms. Any symptom known to one of skill in the art to be associated with Type 2 diabetes can be ameliorated or otherwise modulated as set forth above in the methods described above.
- the symptom or sign is a physical symptom or sign ssuch as increased glucose levels, increased weight gain, frequent urination, unusual thirst, extreme hunger, extreme fatigue, blurred vision, frequent infections, tingling or numbness at the extremities, dry and itchy skin, weight loss, slow-healing sores, and swollen gums.
- the symptom or sign is a physiological symptom or sign selected from the group consisting of increased insulin resistance, increased glucose levels, increased fat mass, decreased metabolic rate, decreased glucose clearance, decreased glucose tolerance, decreased insulin sensitivity, decreased hepatic insulin sensitivity, increased adipose tissue size and weight, increased body fat, and increased body weight.
- the invention provides methods for using a conjugated antisense compound targeted to a GCGR nucleic acid in the preparation of a medicament.
- HBV Hepatitis B
- Hepatitis B is a viral disease transmitted parenterally by contaminated material such as blood and blood products, contaminated needles, sexually and vertically from infected or carrier mothers to their offspring. It is estimated by the World Health Organization that more than 2 billion people have been infected worldwide, with about 4 million acute cases per year, 1 million deaths per year, and 350-400 million chronic carriers ( World Health Organization: Geographic Prevalence of Hepatitis B Prevalence, 2004. http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm ).
- the virus, HBV is a double-stranded hepatotropic virus which infects only humans and non-human primates. Viral replication takes place predominantly in the liver and, to a lesser extent, in the kidneys, pancreas, bone marrow and spleen ( Hepatitis B virus biology. Microbiol Mol Biol Rev. 64: 2000; 51-68 .). Viral and immune markers are detectable in blood and characteristic antigen-antibody patterns evolve over time. The first detectable viral marker is HBsAg, followed by hepatitis B e antigen (HBeAg) and HBV DNA.
- HBsAg hepatitis B e antigen
- HBeAg is a viral marker detectable in blood and correlates with active viral replication, and therefore high viral load and infectivity ( Hepatitis B e antigen-the dangerous end game of hepatitis B. N Engl J Med. 347: 2002; 208-210 ).
- the presence of anti-HBsAb and anti-HBcAb (IgG) indicates recovery and immunity in a previously infected individual.
- the recommended therapies for chronic HBV infection by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include interferon alpha (INF ⁇ ), pegylated interferon alpha-2a (Peg-IFN2a), entecavir, and tenofovir.
- the nucleoside and nucleobase therapies, entecavir and tenofovir are successful at reducing viral load, but the rates of HBeAg seroconversion and HBsAg loss are even lower than those obtained using IFN ⁇ therapy.
- Antisense compounds targeting HBV have been previously disclosed in WO2011/047312 , WO2012/145674 , and WO2012/145697 . Clinical studies are planned to assess the effect of antisense compounds targeting HBV in patients. However, there is still a need to provide patients with additional and more potent treatment options.
- conjugated antisense compounds are targeted to a HBV nucleic acid having the sequence of GENBANK® Accession No. U95551.1, incorporated herein as SEQ ID NO: 12.
- a conjugated antisense compound targeted to SEQ ID NO: 12 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 12.
- a conjugated antisense compound targeted to SEQ ID NO: 12 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 68. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 12 comprises a nucleobase sequence of SEQ ID NO: 68. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- Table 12 Antisense Compounds targeted to HBV SEQ ID NO: 12 ISIS No Target Start Site Sequence (5'-3') Motif SEQ ID NO 505358 1583 GCAGAGGTGAAGCGAAGTGC eeeeeddddddddddeeeee 68
- the invention provides methods for using a conjugated antisense compound targeted to a HBV nucleic acid for modulating the expression of HBV in a subject. In certain embodiments, the expression of HBV is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a HBV nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a HBV-related condition.
- the HBV-related condition includes, but is not limited to, chronic HBV infection, inflammation, fibrosis, cirrhosis, liver cancer, serum hepatitis, jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, and HBV viremia.
- the HBV-related condition may have which may include any or all of the following: flu-like illness, weakness, aches, headache, fever, loss of appetite, diarrhea, jaundice, nausea and vomiting, pain over the liver area of the body, clay- or grey-colored stool, itching all over, and dark-colored urine, when coupled with a positive test for presence of a hepatitis B virus, a hepatitis B viral antigen, or a positive test for the presence of an antibody specific for a hepatitis B viral antigen.
- the subject is at risk for an HBV-related condition.
- the subject has been identified as in need of treatment for an HBV-related condition.
- the invention provides methods for using a conjugated antisense compound targeted to a HBV nucleic acid in the preparation of a medicament.
- PTP1B is a member of a family of PTPs ( Barford, et al., Science 1994. 263: 1397-1404 ) and is a cytosolic enzyme ( Neel and Tonks, Curr. Opin. Cell Biol. 1997. 9: 193-204 ). PTP1B is expressed ubiquitously including tissues that are key regulators of insulin metabolism such as liver, muscle and fat ( Goldstein, Receptor 1993. 3: 1-15 ), where it is the main PTP enzyme.
- PTP1B is considered to be a negative regulator of insulin signaling. PTP1B interacts with and dephosphorylates the insulin receptor, thus attenuating and potentially terminating the insulin signalling transduction ( Goldstein et al., J. Biol. Chem. 2000. 275: 4383-4389 ). The physiological role of PTP1B in insulin signalling has been demonstrated in knockout mice models. Mice lacking the PTP1B gene were protected against insulin resistance and obesity ( Elchebly et al., Science 1999. 283: 1544-1548 ). PTP1B-deficient mice had low adiposity, increased basal metabolic rate as well as total energy expenditure and were protected from diet-induced obesity.
- PTP1B-deficient mice Insulin-stimulated glucose uptake was elevated in skeletal muscle, whereas adipose tissue was unaffected providing evidence that increased insulin sensitivity in PTP1B-deficient mice was tissue-specific ( Klaman et al., Mol. Cell. Biol. 2000. 20: 5479-5489 ). These mice were phenotypically normal and were also resistant to diet-induced obesity, insulin resistance and had significantly lower triglyceride levels on a high-fat diet. Therefore, inhibition of PTP1B in patients suffering from Type II diabetes, metabolic syndrome, diabetic dyslipidemia, or related metabolic diseases would be beneficial.
- Antisense compounds targeting PTP1B have been previously disclosed in WO2001/053528 , WO2002/092772 , WO2004/071407 , WO2006/044531 , WO2012/142458 , WO2006/044531 , and WO2012/142458 .
- An antisense oligonucleotide targeting PTP1B, ISIS-PTP1B Rx recently completed a Phase I clinical study with positive results. However, there is still a need to provide patients with additional and more potent treatment options.
- conjugated antisense compounds are targeted to a PTP1B nucleic acid having the sequence of GENBANK® Accession No. NM_002827.2, incorporated herein as SEQ ID NO: 13 or GENBANK Accession NT_011362.9 truncated from nucleobases 14178000 to 14256000, incorporated herein as SEQ ID NO: 14.
- a conjugated antisense compound targeted to SEQ ID NO: 13 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 13.
- a conjugated antisense compound targeted to SEQ ID NO: 13 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 69-72. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 13 comprises a nucleobase sequence of SEQ ID NOs: 69-72. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a PTP1B nucleic acid for modulating the expression of PTP1B in a subject. In certain embodiments, the expression of PTP1B is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a PTP1B nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has metabolic related diseases, including metabolic syndrome, diabetes mellitus, insulin resistance, diabetic dyslipidemia, hypertriglyceridemia, obesity and weight gain.
- Diabetes mellitus is characterized by numerous physical and physiological symptoms. Any symptom known to one of skill in the art to be associated with Type 2 diabetes can be ameliorated or otherwise modulated as set forth above in the methods described above.
- the symptom is a physical symptom selected from the group consisting of increased glucose levels, increased weight gain, frequent urination, unusual thirst, extreme hunger, extreme fatigue, blurred vision, frequent infections, tingling or numbness at the extremities, dry and itchy skin, weight loss, slow-healing sores, and swollen gums.
- the symptom is a physiological symptom selected from the group consisting of increased insulin resistance, increased fat mass, decreased metabolic rate, decreased glucose clearance, decreased glucose tolerance, decreased insulin sensitivity, decreased hepatic insulin sensitivity, increased adipose tissue size and weight, increased body fat, and increased body weight.
- the invention provides methods for using a conjugated antisense compound targeted to a PTP1B nucleic acid in the preparation of a medicament.
- the STAT (signal transducers and activators of transcription) family of proteins comprises DNA-binding proteins that play a dual role in signal transduction and activation of transcription.
- STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6 there are six distinct members of the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6) and several isoforms (STAT1 ⁇ , STAT1 ⁇ , STAT3 ⁇ and STAT3 ⁇ ).
- the activities of the STATs are modulated by various cytokines and mitogenic stimuli. Binding of a cytokine to its receptor results in the activation of Janus protein tyrosine kinases (JAKs) associated with these receptors.
- JKs Janus protein tyrosine kinases
- the specificity of STAT activation is due to specific cytokines, i.e., each STAT is responsive to a small number of specific cytokines.
- Other non-cytokine signaling molecules such as growth factors, have also been found to activate STATs. Binding of these factors to a cell surface receptor associated with protein tyrosine kinase also results in phosphorylation of STAT.
- STAT3 also acute phase response factor (APRF)
- APRF acute phase response factor
- IL-6 interleukin-6
- EGF epidermal growth factor
- STAT3 has been found to have an important role in signal transduction by interferons ( Yang, C.-H., et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 5568-5572 ).
- ERK2 induces serine phosphorylation and also associates with STAT3 ( Jain, N., et al., Oncogene, 1998, 17, 3157-3167 ).
- STAT3 is expressed in most cell types ( Zhong, Z., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 4806-4810 ). It induces the expression of genes involved in response to tissue injury and inflammation. STAT3 has also been shown to prevent apoptosis through the expression of bcl-2 ( Fukada, T., et al., Immunity, 1996, 5, 449-460 ).
- STAT3 was detected in the mitochondria of transformed cells, and was shown to facilitate glycolytic and oxidative phosphorylation activities similar to that of cancer cells ( Gough, D.J., et al., Science, 2009, 324, 1713-1716 ).
- the inhibition of STAT3 in the mitochondria impaired malignant transformation by activated Ras.
- the data confirms a Ras-mediated transformation function for STAT3 in the mitochondria in addition to its nuclear roles.
- Antisense compounds targeting STAT3 have been previously disclosed in WO2012/135736 and WO2005/083124 .
- An antisense oligonucleotide targeting STAT3, ISIS-STAT3 Rx is currently in Phase 1/2 clinical trials to study its effectiveness in treating subjects with cancer.
- conjugated antisense compounds are targeted to a STAT3 nucleic acid having the sequence of GENBANK® Accession No. NM_139276.2, incorporated herein as SEQ ID NO: 15.
- a conjugated antisense compound targeted to SEQ ID NO: 15 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 15.
- a conjugated antisense compound targeted to SEQ ID NO: 15 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NO: 73. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 15 comprises a nucleobase sequence of SEQ ID NO: 73. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- Table 14 Antisense Compounds targeted to STAT3 SEQ ID NO: 15 ISIS No Target Start Site Sequence (5'-3') Motif SEQ ID NO 481464 3016 CTATTTGGATGTCAGC kkkddddddddddkkk 73
- the invention provides methods for using a conjugated antisense compound targeted to a STAT3 nucleic acid for modulating the expression of STAT3 in a subject. In certain embodiments, the expression of STAT3 is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a STAT3 nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a hyperproliferative disease, disorder or condition.
- hyperproliferative disease, disorder, and condition include cancer as well as associated malignancies and metastases.
- such cancers include lung cancer, including non small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer, multiple myeloma, hepatocellular carcinoma (HCC), glioblastoma, ovarian cancer, osteosarcoma, head and neck cancer, breast cancer, epidermoid carcinomas, intestinal adenomas, prostate cancer, and gastric cancer.
- NSCLC non small cell lung cancer
- HPC hepatocellular carcinoma
- glioblastoma ovarian cancer
- osteosarcoma head and neck cancer
- breast cancer epidermoid carcinomas
- intestinal adenomas prostate cancer
- gastric cancer gastric cancer
- the invention provides methods for using a conjugated antisense compound targeted to a STAT3 nucleic acid in the preparation of a medicament.
- TRR Transthyretin
- TTR also known as prealbumin, hyperthytoxinemia, dysprealbuminemic, thyroxine; senile systemic amyloidosis, amyloid polyneuropathy, amyloidosis I, PALB; dystransthyretinemic, HST2651; TBPA; dysprealbuminemic euthyroidal hyperthyroxinemia
- prealbumin hyperthytoxinemia, dysprealbuminemic, thyroxine
- senile systemic amyloidosis amyloid polyneuropathy, amyloidosis I, PALB
- dystransthyretinemic HST2651
- TBPA dysprealbuminemic euthyroidal hyperthyroxinemia
- TTR is a homotetramer; point mutations and misfolding of the protein leads to deposition of amyloid fibrils and is associated with disorders, such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiopathy (FAC).
- SSA senile systemic amyloidosis
- FAP familial amyloid polyneuropathy
- FAC familial amyloid cardiopathy
- TTR is synthesized primarily by the liver and the choroid plexus of the brain and, to a lesser degree, by the retina in humans ( Palha, Clin Chem Lab Med, 2002, 40, 1292-1300 ). Transthyretin that is synthesized in the liver is secreted into the blood, whereas transthyretin originating in the choroid plexus is destined for the CSF. In the choroid plexus, transthyretin synthesis represents about 20% of total local protein synthesis and as much as 25% of the total CSF protein ( Dickson et al., J Biol Chem, 1986, 261, 3475-3478 ).
- TTR amyloidosis is not a rare endemic disease as previously thought, and may affect as much as 25% of the elderly population ( Tanskanen et al, Ann Med. 2008;40(3):232-9 ).
- TTR was identified as the major protein component in the amyloid deposits of FAP patients ( Costa et al, Proc. Natl. Acad. Sci. USA 1978, 75:4499-4503 ) and later, a substitution of methionine for valine at position 30 of the protein was found to be the most common molecular defect causing the disease ( Saraiva et al, J. Clin. Invest. 1984, 74: 104-119 ).
- FAP widespread systemic extracellular deposition of TTR aggregates and amyloid fibrils occurs throughout the connective tissue, particularly in the peripheral nervous system ( Sousa and Saraiva, Prog. Neurobiol. 2003, 71: 385-400 ).
- axonal degeneration occurs, starting in the unmyelinated and myelinated fibers of low diameter, and ultimately leading to neuronal loss at ganglionic sites.
- Antisense compounds targeting TTR have been previously disclosed in US2005/0244869 , WO2010/017509 , and WO2011/139917 .
- An antisense oligonucleotide targeting TTR, ISIS-TTR Rx is currently in Phase 2/3 clinical trials to study its effectiveness in treating subjects with Familial Amyloid Polyneuropathy.
- ISIS-TTR Rx is currently in Phase 2/3 clinical trials to study its effectiveness in treating subjects with Familial Amyloid Polyneuropathy.
- conjugated antisense compounds are targeted to a TTR nucleic acid having the sequence of GENBANK® Accession No. NM_000371.3, incorporated herein as SEQ ID NO: 16.
- a conjugated antisense compound targeted to SEQ ID NO: 16 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 16.
- a conjugated antisense compound targeted to SEQ ID NO: 16 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 74-81. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 16 comprises a nucleobase sequence of SEQ ID NO: 74-81. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a TTR nucleic acid for modulating the expression of TTR in a subject. In certain embodiments, the expression of TTR is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a TTR nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a transthyretin related disease, disorder or condition, or symptom thereof.
- the transthyretin related disease, disorder or condition is transthyretin amyloidosis.
- Transthyretin-related amyloidosis or “transthyretin amyloidosis” or “Transthyretin amyloid disease”
- Transthyretin amyloid disease is any pathology or disease associated with dysfunction or dysregulation of transthyretin that result in formation of transthyretin-containing amyloid fibrils.
- Transthyretin amyloidosis includes, but is not limited to, hereditary TTR amyloidosis, leptomeningeal amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy, familial oculoleptomeningeal amyloidosis, senile cardiac amyloidosis, or senile systemic amyloidosis.
- FAP familial amyloid polyneuropathy
- FAP familial amyloid cardiomyopathy
- familial oculoleptomeningeal amyloidosis familial oculoleptomeningeal amyloidosis
- senile cardiac amyloidosis or senile systemic amyloidosis.
- the invention provides methods for using a conjugated antisense compound targeted to a TTR nucleic acid in the preparation of a medicament.
- PCSK9 also known as Proprotein convertase subtilisin kexin 9
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1P/SKI-1
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1P/SKI-1
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1P/SKI-1
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1P/SKI-1
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1P/SKI-1
- PCSK1-PCSK8 also called PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, and S1
- PCSK9 has been proposed to play a role in cholesterol metabolism.
- PCSK9 mRNA expression is down-regulated by dietary cholesterol feeding in mice ( Maxwell, K. N., (2003) J. Lipid Res. 44, 2109-2119 ), up-regulated by statins in HepG2 cells ( Dubuc, G., (2004) Arterioscler. Thromb. Vasc. Biol. 24, 1454-1459 ), and up-regulated in sterol regulatory element binding protein (SREBP) transgenic mice ( Horton, J.
- PCSK9 may also play a role in determining LDL cholesterol levels in the general population, because single-nucleotide polymorphisms (SNPs) have been associated with cholesterol levels in a Japanese population ( Shioji, K., (2004) J. Hum. Genet. 49, 109-114 ).
- SNPs single-nucleotide polymorphisms
- Antisense compounds targeting PCSK9 have been previously disclosed in U.S. Patents 8,084,437 ; 8,093,222 ; 8,664,190 ; and International applications WO 2008/066776 and WO 2009/148605 . However, there is still a need to provide patients with additional and more potent treatment options.
- conjugated antisense compounds are targeted to a PCSK9 nucleic acid having the sequence of GENBANK® Accession, incorporated herein as SEQ ID NO: 160.
- a conjugated antisense compound targeted to SEQ ID NO: 160 is at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 160.
- a conjugated antisense compound targeted to SEQ ID NO: 160 comprises an at least 8 consecutive nucleobase sequence of SEQ ID NOs: 156-159. In certain embodiments, a conjugated antisense compound targeted to SEQ ID NO: 160 comprises a nucleobase sequence of SEQ ID NO: 156-159. In certain embodiments, such conjugated antisense compounds comprise a conjugate comprising 1-3 GalNAc ligands. In certain embodments, such antisense compounds comprise a conjugate disclosed herein.
- the invention provides methods for using a conjugated antisense compound targeted to a PCSK9 nucleic acid for modulating the expression of PCSK9 in a subject. In certain embodiments, the expression of PCSK9 is reduced.
- the invention provides methods for using a conjugated antisense compound targeted to a PCSK9 nucleic acid in a pharmaceutical composition for treating a subject.
- the subject has a PCSK9 related disease, disorder or condition, or symptom thereof.
- the PCSK9 related disease, disorder or condition is a metabolic or cardiovascular disease.
- the invention provides methods for using a conjugated antisense compound targeted to a PCSK9 nucleic acid in the preparation of a medicament.
- conjugated antisense compounds comprise antisense compounds having the nucleobase sequence of the antisense compounds in Table 16 below attached to a GalNAc conjugate. In certain embodiments, conjugated antisense compounds comprise antisense compounds having the nucleobase sequence and chemical modifications of the antisense compounds in Table 16 below attached to a GalNAc conjugate. All internucleoside linkages are phosphorothioate internucleoside linkages unless otherwise indicated.
- a subscript "l” indicates an LNA bicyclic nucleoside.
- a subscript "d” indicates a 2'-deoxy nucleoside.
- a subscript "e” indicates a 2'-MOE modified nucleoside.
- a subscript "v” indicates a 2-amino-2'-deoxyadenosine.
- Table 16 Sequence 5' to 3' Target Motif Chemistry Internucleoside Linkages SEQ ID NO. HIF-1 ⁇ 3-9-3-1 LNA/deoxy phosphorothioate 82 Survivin 4-8-3-1 LNA/deoxy phosphorothioate 83 Androgen Receptor 3-10-3 LNA/deoxy phosphorothioate 84 G l C l A d T d T d G d G d T d A d T d T l C l A l ApoB 2-8-3 LNA/deoxy phosphorothioate 85 ApoB 5-10-5 LNA/deoxy phosphorothioate 86 ApoB 3-10-3 LNA/deoxy phosphorothioate 87 C l A l G l C d A d T d T d G d T d A d T d T l C
- a compound comprises an antisense oligonucleotide targeted to eukaryotic Initiation Factor 4E (eIF4E) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to dIF4E are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to dIF4E are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to eIF4E suitable for conjugation include but are not limited to those disclosed in US 7,425,544 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 18-122 disclosed in US 7,425,544 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense strand having a nucleobase sequence of any of SEQ ID NOs: 212-459 disclosed in US 7,425,544 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Signal Transducer and Activator of Transcription 3 (STAT3) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to STAT3 are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to STAT3 are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to STAT3 suitable for conjugation include but are not limited to those disclosed in WO 2012/135736 , WO 2005/083124 , and US 6,727,064 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 9-426, 430-442, 445-464, 471-498, 500-1034, 1036-1512, and 1541-2757 disclosed in WO 2012/135736 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 2-81, 108-150, and 159-381 disclosed in WO 2005/083124 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 2-81 and 108-150 disclosed in US 6,727,064 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to glucocorticoid receptor (GCCR) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to GCCR are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to GCCR are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to GCCR suitable for conjugation include but are not limited to those disclosed in WO 2005/071080 , WO 2007/035759 , and WO 2007/136988 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 30-216, and 306-310 disclosed in WO 2005/071080 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 26-113 disclosed in WO 2007/035759 and a conjugate group disclosed herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 413-485 disclosed in WO 2007/136988 and a conjugate group disclosed herein.
- a compound comprises an antisense oligonucleotide targeted to glucagon receptor (GCGR) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to GCGR are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to GCGR are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to GCGR suitable for conjugation include but are not limited to those disclosed in US 7,750,142 ; US 7,399,853 ; WO 2007/035771 ; and WO 2007/134014 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 20-399 disclosed in US 7,750,142 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 20-399 disclosed in US 7,399,853 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of SEQ ID NO: 2 disclosed in WO 2007/035771 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs: 486-680 disclosed in WO 2007/134014 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Protein Tyrosine Phosphatase 1B (PTP1B) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to PTP1B are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to PT1B are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to PTP1B suitable for conjugation include but are not limited to those disclosed in US 7,563,884 and WO 2007/131237 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 17-96 and 244-389 disclosed in US 7,563,884 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 886-1552 disclosed in WO 2007/131237 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Fibroblast Growth Factor Receptor 4 (FGFR4) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to FGFR4 are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to FGFR4 are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to FGFR4 suitable for conjugation include but are not limited to those disclosed in WO 2009/046141 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 21-24, 28, 29, 36, 38, 39, 43, 48, 51, 54-56, 58-60, 64-66, and 92-166 disclosed in WO 2009/046141 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to alpha-1-antitrypsin (A1AT) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to A1AT are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to A1AT are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to A1AT suitable for conjugation include but are not limited to those disclosed in WO 2013/142514 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 20-41 disclosed in WO 2013/142514 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Factor VII known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to Factor VII are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to Factor VII are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to Factor VII suitable for conjugation include but are not limited to those disclosed in WO 2013/119979 and WO 2009/061851 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 21-659 disclosed in WO 2013/119979 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 4-159 and 168-611 disclosed in WO 2009/061851 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Factor XI known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to Factor XI are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to Factor XI are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to Factor XI suitable for conjugation include but are not limited to those disclosed in WO 2010/045509 and WO 2010/121074 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 15-270 disclosed in WO 2010/045509 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 15-270 disclosed in WO 2010/121074 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Hepatitis B Virus (HBV) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to HBV are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to HBV are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to HBV suitable for conjugation include but are not limited to those disclosed in WO 2012/145697 and WO 2012/145697 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 5-310, 321-802, 804-1272, 1288-1350, 1364-1372, 1375, 1376, and 1379 disclosed in WO 2012/145697 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 14-22 disclosed in WO 2011/ 047312 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to transthyretin (TTR) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to TTR are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to TTR are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to TTR suitable for conjugation include but are not limited to those disclosed in WO 2011/139917 and US 8,101,743 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 8-160, 170-177 disclosed in WO 2011/139917 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 12-89 disclosed in US 8,101,743 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence complementary to a preferred target segment of any of SEQ ID NOs 90-133 disclosed in US 8,101,743 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to apolipoprotein(a) (apo(a)) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to apo(a) are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to apo(a) are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to apo(a) suitable for conjugation include but are not limited to those disclosed in WO 2013/177468 ; US 8,673,632 ; US 7,259,150 ; and US Patent Application Publication No.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 12-130, 133, 134 disclosed in WO 2013/177468 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 11-45 and 85-96 disclosed in US 8,673,632 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 11-45 disclosed in US 7,259,150 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 7-41 disclosed in US Patent Application Publication No. US 2004/0242516 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Apolipoprotein B (ApoB) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to ApoB are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to ApoB are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to ApoB suitable for conjugation include but are not limited to those disclosed in US Patent Application Publication Nos. US 2010/0331390 , US 2009/0306180 , and US 2005/0009088 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 disclosed in US 2010/0331390 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 16-213 disclosed in US 2009/0306180 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 17-70, 124-317, 319-333, 335-502, 504-804, and 864-887 disclosed in US 2005/0009088 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to Apolipoprotein C-III (ApoC-III) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to ApoC-III are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to ApoC-III are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to ApoC-III suitable for conjugation include but are not limited to those disclosed in US Patent Application Publication No. US 2013/0317085 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 19-96 and 209-221 disclosed in US 2013/0317085 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to PCSK9 are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to PCSK9 are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to PCSK9 suitable for conjugation include but are not limited to those disclosed in US 8,143,230 and US 8,664,190 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 329-403 disclosed in US 8,143,230 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 4-455 and 458-461 disclosed in US 8,664,190 and a conjugate group described herein.
- a compound comprises an antisense oligonucleotide targeted to C-reactive protein (CRP) known in the art and a conjugate group described herein.
- antisense oligonucleotides targeted to CRP are RNAi (siRNA or ssRNA) compounds.
- antisense oligonucleotides targeted to CRP are RNase H based antisense compounds. Examples of antisense oligonucleotides targeted to CRP suitable for conjugation include but are not limited to those disclosed in WO 2003/010284 , WO 2005/005599 , and WO 2007/143317 .
- a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 10-63 disclosed in WO 2003/010284 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 19-72, 76-259, and 598-613 disclosed in WO 2005/005599 and a conjugate group described herein. In certain embodiments, a compound comprises an antisense oligonucleotide having a nucleobase sequence of any of SEQ ID NOs 409-412 disclosed in WO 2007/143317 and a conjugate group described herein.
- the present disclosure provides pharmaceutical compositions comprising one or more antisense compound.
- such pharmaceutical composition comprises a suitable pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition comprises a sterile saline solution and one or more antisense compound.
- such pharmaceutical composition consists of a sterile saline solution and one or more antisense compound.
- the sterile saline is pharmaceutical grade saline.
- a pharmaceutical composition comprises one or more antisense compound and sterile water.
- a pharmaceutical composition consists of one or more antisense compound and sterile water.
- the sterile saline is pharmaceutical grade water.
- a pharmaceutical composition comprises one or more antisense compound and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one or more antisense compound and sterile phosphate-buffered saline (PBS). In certain embodiments, the sterile saline is pharmaceutical grade PBS.
- antisense compounds may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
- Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
- compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters.
- pharmaceutical compositions comprising antisense compounds comprise one or more oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof.
- the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.
- Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
- a prodrug can include the incorporation of additional nucleosides at one or both ends of an oligonucleotide which are cleaved by endogenous nucleases within the body, to form the active antisense oligonucleotide.
- Lipid moieties have been used in nucleic acid therapies in a variety of methods.
- the nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids.
- DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid.
- a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue.
- a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue.
- a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.
- compositions provided herein comprise one or more modified oligonucleotides and one or more excipients.
- excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
- a pharmaceutical composition provided herein comprises a delivery system.
- delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
- a pharmaceutical composition provided herein comprises one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present disclosure to specific tissues or cell types.
- pharmaceutical compositions include liposomes coated with a tissue-specific antibody.
- a pharmaceutical composition provided herein comprises a co-solvent system.
- co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
- co-solvent systems are used for hydrophobic compounds.
- a non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM and 65% w/v polyethylene glycol 300.
- the proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
- co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
- a pharmaceutical composition provided herein is prepared for oral administration. In certain embodiments, pharmaceutical compositions are prepared for buccal administration.
- a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
- a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
- other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
- injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
- compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
- Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
- a pharmaceutical composition is prepared for transmucosal administration.
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- a pharmaceutical composition provided herein comprises an oligonucleotide in a therapeutically effective amount.
- the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
- one or more modified oligonucleotide provided herein is formulated as a prodrug.
- a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically more active form of an oligonucleotide.
- prodrugs are useful because they are easier to administer than the corresponding active form.
- a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
- a prodrug may have improved solubility compared to the corresponding active form.
- prodrugs are less water soluble than the corresponding active form.
- a prodrug is an ester.
- the ester is metabolically hydrolyzed to carboxylic acid upon administration.
- the carboxylic acid containing compound is the corresponding active form.
- a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
- the peptide is cleaved upon administration to form the corresponding active form.
- the present disclosure provides compositions and methods for reducing the amount or activity of a target nucleic acid in a cell.
- the cell is in an animal.
- the animal is a mammal.
- the animal is a rodent.
- the animal is a primate.
- the animal is a non-human primate.
- the animal is a human.
- the present disclosure provides methods of administering a pharmaceutical composition comprising an oligonucleotide of the present disclosure to an animal.
- Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intracerebroventricular, intraperitoneal, intranasal, intraocular, intratumoral, and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
- pharmaceutical intrathecals are administered to achieve local rather than systemic exposures.
- pharmaceutical compositions may be injected directly in the area of desired effect (e.g., into the liver).
- compositions, and methods herein are described as “comprising exactly” or “comprises exactly” a particular number of a particular element or feature. Such descriptions are used to indicate that while the compound, composition, or method may comprise additional other elements, the number of the particular element or feature is the identified number.
- a conjugate comprising exactly one GalNAc is a conjugate that contains one and only one GalNAc, though it may contain other elements in addition to the one GalNAc.
- RNA nucleoside comprising a 2'-OH sugar moiety and a thymine base
- RNA methylated uracil
- nucleic acid sequences provided herein are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases.
- an oligonucleotide having the nucleobase sequence "ATCGATCG” encompasses any oligonucleotides having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence "AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligonucleotides having other modified bases, such as "AT me CGAUCG,” wherein me C indicates a cytosine base comprising a methyl group at the 5-position.
- Bx is a heterocyclic base
- Compound 11 was prepared as per the procedures illustrated in Example 3.
- Compound 14 is commercially available.
- Compound 17 was prepared using similar procedures reported by Rensen et al., J. Med. Chem., 2004, 47, 5798-5808 .
- Compound 24 was prepared as per the procedures illustrated in Example 6.
- Compound 24 is prepared as per the procedures illustrated in Example 6.
- GalNAc 3 cluster portion of the conjugate group GalNAc 3 -1 (GalNAC 3 -1 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAC 3 -1 a has the formula:
- Oligomeric Compound 29 comprising GalNAc 3 -1 at the 3' terminus was prepared using standard procedures in automated DNA/RNA synthesis (see Dupouy et al., Angew. Chem. Int. Ed., 2006, 45, 3623-3627 ).
- Phosphoramidite building blocks, Compounds 1 and 1a were prepared as per the procedures illustrated in Example 1.
- the phosphoramidites illustrated are meant to be representative and not intended to be limiting as other phosphoramidite building blocks can be used to prepare oligomeric compounds having a predetermined sequence and composition.
- the order and quantity of phosphoramidites added to the solid support can be adjusted to prepare gapped oligomeric compounds as described herein. Such gapped oligomeric compounds can have predetermined composition and base sequence as dictated by any given target.
- Example 10 General preparation conjugated ASOs comprising GalNAc 3 -1 at the 5' terminus, Compound 34
- the UnylinkerTM 30 is commercially available. Oligomeric Compound 34 comprising a GalNAc 3 -1 cluster at the 5' terminus is prepared using standard procedures in automated DNA/RNA synthesis (see Dupouy et al., Angew. Chem. Int. Ed., 2006, 45, 3623-3627 ). Phosphoramidite building blocks, Compounds 1 and 1a were prepared as per the procedures illustrated in Example 1. The phosphoramidites illustrated are meant to be representative and not intended to be limiting as other phosphoramidite building blocks can be used to prepare an oligomeric compound having a predetermined sequence and composition. The order and quantity of phosphoramidites added to the solid support can be adjusted to prepare gapped oligomeric compounds as described herein. Such gapped oligomeric compounds can have predetermined composition and base sequence as dictated by any given target.
- Compounds 48 and 49 are commercially available.
- Compounds 17 and 47 are prepared as per the procedures illustrated in Examples 4 and 15 .
- Example 19 General method for the preparation of conjugated ASOs comprising GalNAc 3 -1 at the 3' position via solid phase techniques (preparation of ISIS 647535, 647536 and 651900)
- reagents and solutions used for the synthesis of oligomeric compounds are purchased from commercial sources.
- Standard phosphoramidite building blocks and solid support are used for incorporation nucleoside residues which include for example T, A, G, and m C residues.
- a 0.1 M solution of phosphoramidite in anhydrous acetonitrile was used for ⁇ -D-2'-deoxyribonucleoside and 2'-MOE.
- the ASO syntheses were performed on ABI 394 synthesizer (1-2 ⁇ mol scale) or on GE Healthcare Bioscience ⁇ KTA oligopilot synthesizer (40-200 ⁇ mol scale) by the phosphoramidite coupling method on an GalNAc 3 -1 loaded VIMAD solid support (110 ⁇ mol/g, Guzaev et al ., 2003) packed in the column.
- the phosphoramidites were delivered 4 fold excess over the loading on the solid support and phosphoramidite condensation was carried out for 10 min. All other steps followed standard protocols supplied by the manufacturer.
- a solution of 6% dichloroacetic acid in toluene was used for removing dimethoxytrityl (DMT) group from 5'-hydroxyl group of the nucleotide.
- 4,5-Dicyanoimidazole (0.7 M) in anhydrous CH 3 CN was used as activator during coupling step.
- Phosphorothioate linkages were introduced by sulfurization with 0.1 M solution of xanthane hydride in 1:1 pyridine/CH 3 CN for a contact time of 3 minutes.
- a solution of 20% tert -butylhydroperoxide in CH 3 CN containing 6% water was used as an oxidizing agent to provide phosphodiester internucleoside linkages with a contact time of 12 minutes.
- the cyanoethyl phosphate protecting groups were deprotected using a 1:1 (v/v) mixture of triethylamine and acetonitrile with a contact time of 45 minutes.
- the solid-support bound ASOs were suspended in aqueous ammonia (28-30 wt %) and heated at 55 °C for 6 h.
- the unbound ASOs were then filtered and the ammonia was boiled off.
- the residue was desalted by HPLC on a reverse phase column to yield the desired ASOs in an isolated yield of 15-30% based on the initial loading on the solid support.
- the ASOs were characterized by ion-pair-HPLC coupled MS analysis with Agilent 1100 MSD system.
- Antisense oligonucleotides not comprising a conjugate were synthesized using standard oligonucleotide synthesis procedures well known in the art.
- each of the three antisense compounds targeting ApoC III had the same nucleobase sequence; ISIS 304801 is a 5-10-5 MOE gapmer having all phosphorothioate linkages; ISIS 647535 is the same as ISIS 304801, except that it had a GalNAc 3 -1 conjugated at its 3'end; and ISIS 647536 is the same as ISIS 647535 except that certain internucleoside linkages of that compound are phosphodiester linkages. As further summarized in Table 17, two separate antisense compounds targeting SRB-1 were synthesized.
- ISIS 440762 was a 2-10-2 cEt gapmer with all phosphorothioate internucleoside linkages; ISIS 651900 is the same as ISIS 440762, except that it included a GalNAc 3 -1 at its 3'-end.
- Table 17 Modified ASO targeting ApoC III and SRB-1 ASO Sequence (5' to 3') Target CalCd Mass Observed Mass SEQ ID No.
- ISIS 304801 A es G es m C es T es T es m C ds T ds T ds G ds T ds m C ds m C ds A ds G ds m C ds T es T es A es T e ApoC III 7165.4 7164.4 32 ISIS 647535 ApoC III 9239.5 9237.8 111 ISIS 647536 ApoC III 9142.9 9140.8 111 ISIS 440762 T ks m C ks A ds G ds T ds m C ds A ds T ds G ds A ds m C ds T ds T ks m C k SRB-1 4647.0 4646.4 104 ISIS 651900 T ks m C ks A ds G ds T dS m C ds A
- GalNAc 3 -1 indicates a conjugate group having the structure shown previously in Example 9. Note that GalNAc 3 -1 comprises a cleavable adenosine which links the ASO to remainder of the conjugate, which is designated " GalNAc 3 -1 a . " This nomenclature is used in the above table to show the full nucleobase sequence, including the adenosine, which is part of the conjugate.
- the hPBMC assay was performed using BD Vautainer CPT tube method.
- a sample of whole blood from volunteered donors with informed consent at US HealthWorks clinic (Faraday & El Camino Real, Carlsbad) was obtained and collected in 4-15 BD Vacutainer CPT 8 ml tubes (VWR Cat.# BD362753).
- the approximate starting total whole blood volume in the CPT tubes for each donor was recorded using the PBMC assay data sheet.
- the blood sample was remixed immediately prior to centrifugation by gently inverting tubes 8-10 times.
- CPT tubes were centrifuged at rt (18-25 °C) in a horizontal (swing-out) rotor for 30 min. at 1500-1800 RCF with brake off (2700 RPM Beckman Allegra 6R).
- the cells were retrieved from the buffy coat interface (between Ficoll and polymer gel layers); transferred to a sterile 50 ml conical tube and pooled up to 5 CPT tubes/50 ml conical tube/donor.
- the cells were then washed twice with PBS (Ca ++ , Mg ++ free; GIBCO).
- the tubes were topped up to 50 ml and mixed by inverting several times.
- the sample was then centrifuged at 330 x g for 15 minutes at rt (1215 RPM in Beckman Allegra 6R) and aspirated as much supernatant as possible without disturbing pellet.
- the cell pellet was dislodged by gently swirling tube and resuspended cells in RPMI+10% FBS+pen/strep ( ⁇ 1 ml / 10 ml starting whole blood volume).
- a 60 ⁇ l sample was pipette into a sample vial (Beckman Coulter) with 600 ⁇ l VersaLyse reagent (Beckman Coulter Cat# A09777) and was gently vortexed for 10-15 sec. The sample was allowed to incubate for 10 min. at rt and being mixed again before counting.
- the cell suspension was counted on Vicell XR cell viability analyzer (Beckman Coulter) using PBMC cell type (dilution factor of 1:11 was stored with other parameters). The live cell/ml and viability were recorded. The cell suspension was diluted to 1 x 10 7 live PBMC/ml in RPMI+ 10% FBS+pen/strep.
- the cells were plated at 5 x 10 5 in 50 ⁇ l/well of 96-well tissue culture plate (Falcon Microtest). 50 ⁇ l/well of 2x concentration oligos/controls diluted in RPMI+10% FBS+pen/strep. was added according to experiment template (100 ⁇ l/well total). Plates were placed on the shaker and allowed to mix for approx. 1 min. After being incubated for 24 hrs at 37 °C; 5% CO 2 , the plates were centrifuged at 400 x g for 10 minutes before removing the supernatant for MSD cytokine assay (i.e. human IL-6, IL-10, IL-8 and MCP-1).
- MSD cytokine assay i.e. human IL-6, IL-10, IL-8 and MCP-1).
- Compound 76 was prepared according to published procedures reported by Shchepinov et al., Nucleic Acids Research, 1997, 25(22), 4447-4454 .
- Example 37 General method for the preparation of conjugated oligomeric compound 82 comprising a phosphodiester linked GalNAc 3 -2 conjugate at 5' terminus via solid support (Method I)
- GalNAc 3 -2 has the structure:
- GalNAc 3 cluster portion of the conjugate group GalNAc 3 -2 (GalNAc 3 -2 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -2 a has the formula:
- the VIMAD-bound oligomeric compound 79b was prepared using standard procedures for automated DNA/RNA synthesis (see Dupouy et al., Angew. Chem. Int. Ed., 2006, 45, 3623-3627 ).
- the phosphoramidite Compounds 56 and 60 were prepared as per the procedures illustrated in Examples 27 and 28, respectively.
- the phosphoramidites illustrated are meant to be representative and not intended to be limiting as other phosphoramidite building blocks including but not limited those presented in the specification herein can be used to prepare an oligomeric compound having a phosphodiester linked conjugate group at the 5' terminus.
- the order and quantity of phosphoramidites added to the solid support can be adjusted to prepare the oligomeric compounds as described herein having any predetermined sequence and composition.
- Example 39 General method for the preparation of oligomeric compound 83h comprising a GalNAc 3 - 3 Conjugate at the 5' Terminus (GalNAc 3 -1 modified for 5' end attachment) via Solid Support
- Compound 18 was prepared as per the procedures illustrated in Example 4.
- Compounds 83a and 83b are commercially available.
- Oligomeric Compound 83e comprising a phosphodiester linked hexylamine was prepared using standard oligonucleotide synthesis procedures. Treatment of the protected oligomeric compound with aqueous ammonia provided the 5'-GalNAc 3 -3 conjugated oligomeric compound (83h).
- GalNAc 3 -3 has the structure:
- GalNAc 3 -3 a The GalNAc 3 cluster portion of the conjugate group GalNAc 3 -3 (GalNAc 3 -3 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -3 a has the formula:
- Example 40 General method for the preparation of oligomeric compound 89 comprising a phosphodiester linked GalNAc 3 -4 conjugate at the 3' terminus via solid support
- GalNAc 3 -4 has the structure:
- CM is a cleavable moiety.
- cleavable moiety is:
- GalNAc 3 cluster portion of the conjugate group GalNAc 3 -4 (GalNAc 3 -4 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -4 a has the formula:
- the protected Unylinker functionalized solid support Compound 30 is commercially available.
- Compound 84 is prepared using procedures similar to those reported in the literature ( see Shchepinov et al., Nucleic Acids Research, 1997, 25(22), 4447-4454 ; Shchepinov et al., Nucleic Acids Research, 1999, 27, 3035-3041 ; and Hornet et al., Nucleic Acids Research, 1997, 25, 4842-4849 ).
- the phosphoramidite building blocks, Compounds 60 and 79a are prepared as per the procedures illustrated in Examples 28 and 36.
- the phosphoramidites illustrated are meant to be representative and not intended to be limiting as other phosphoramidite building blocks can be used to prepare an oligomeric compound having a phosphodiester linked conjugate at the 3' terminus with a predetermined sequence and composition.
- the order and quantity of phosphoramidites added to the solid support can be adjusted to prepare the oligomeric compounds as described herein having any predetermined sequence and composition.
- Compound 109a was treated to the same conditions as for compounds 101a-d (Example 47), to give Compound 110a in 30-60% yield. LCMS and proton NMR was consistent with the structure. Alternatively, Compound 110b can be prepared in a similar manner starting with Compound 109b.
- Example 46 General Procedure for Conjugation with PFP Esters (Oligonucleotide 111); Preparation of ISIS 666881 (GalNAc 3 -10)
- a 5'-hexylamino modified oligonucleotide was synthesized and purified using standard solid-phase oligonucleotide procedures.
- the 5'-hexylamino modified oligonucleotide was dissolved in 0.1 M sodium tetraborate, pH 8.5 (200 ⁇ L) and 3 equivalents of a selected PFP esterified GalNAc 3 cluster dissolved in DMSO (50 ⁇ L) was added. If the PFP ester precipitated upon addition to the ASO solution DMSO was added until all PFP ester was in solution. The reaction was complete after about 16 h of mixing at room temperature.
- the resulting solution was diluted with water to 12 mL and then spun down at 3000 rpm in a spin filter with a mass cut off of 3000 Da. This process was repeated twice to remove small molecule impurities.
- the solution was then lyophilized to dryness and redissolved in concentrated aqueous ammonia and mixed at room temperature for 2.5 h followed by concentration in vacuo to remove most of the ammonia.
- the conjugated oligonucleotide was purified and desalted by RP-HPLC and lyophilized to provide the GalNAc 3 conjugated oligonucleotide.
- Oligonucleotide 111 is conjugated with GalNAc 3 -10.
- the GalNAc 3 cluster portion of the conjugate group GalNAc 3 -10 (GalNAc 3 -10 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- the structure of GalNAc 3 -10 (GalNAc 3 -10 a -CM-) is shown below:
- ISIS 666881 was prepared. 5'-hexylamino modified oligonucleotide, ISIS 660254, was synthesized and purified using standard solid-phase oligonucleotide procedures. ISIS 660254 (40 mg, 5.2 ⁇ mol) was dissolved in 0.1 M sodium tetraborate, pH 8.5 (200 ⁇ L) and 3 equivalents PFP ester (Compound 110a) dissolved in DMSO (50 ⁇ L) was added. The PFP ester precipitated upon addition to the ASO solution requiring additional DMSO (600 ⁇ L) to fully dissolve the PFP ester. The reaction was complete after 16 h of mixing at room temperature.
- the solution was diluted with water to 12 mL total volume and spun down at 3000 rpm in a spin filter with a mass cut off of 3000 Da. This process was repeated twice to remove small molecule impurities.
- the solution was lyophilized to dryness and redissolved in concentrated aqueous ammonia with mixing at room temperature for 2.5 h followed by concentration in vacuo to remove most of the ammonia.
- the conjugated oligonucleotide was purified and desalted by RP-HPLC and lyophilized to give ISIS 666881 in 90% yield by weight (42 mg, 4.7 ⁇ mol).
- the dichloromethane solution was concentrated to dryness and purified with silica gel column chromatography and eluted with 5 to 10 % MeOH in dichloromethane to yield compound 118 (0.51 g, 79%).
- the structure was confirmed by LCMS and 1 H and 1 H and 19 F NMR.
- Oligomeric Compound 119 comprising a GalNAc 3 -7 conjugate group, was prepared using the general procedures illustrated in Example 46.
- the GalNAc 3 cluster portion of the conjugate group GalNAc 3 -7 (GalNAc 3 -7 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -7 (GalNAc 3 -7 a -CM-) is shown below:
- Trifluoroacetic acid (12 mL) was added to a solution of compound 127 (1.57 g, 2.02 mmol) in dichloromethane (12 mL) and stirred at room temperature for 1 h.
- the reaction mixture was co-evaporated with toluene (30 mL) under reduced pressure to dryness.
- the residue obtained was co-evaporated twice with acetonitrile (30 mL) and toluene (40 mL) to yield Compound 128 (1.67 g) as trifluoro acetate salt and used for next step without further purification.
- LCMS and 1 H NMR were consistent with structure. Mass m / z 478.2 [M + H] + .
- Oligomeric Compound 132 comprising a GalNAc 3 -5 conjugate group, was prepared using the general procedures illustrated in Example 46.
- the GalNAc 3 cluster portion of the conjugate group GalNAc 3 -5 (GalNAc 3 -5 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -5 (GalNAc 3 -5 a -CM-) is shown below:
- the suspension was allowed to shake for 3 h.
- the reaction mixture was drained and the resin was washed with acetonitrile, DMF and DCM.
- the resin was capped by suspending in an acetic anhydride solution for ten minutes three times.
- the solid support bound compound 141 was synthesized using iterative Fmoc-based solid phase peptide synthesis methods. A small amount of solid support was withdrawn and suspended in aqueous ammonia (28-30 wt%) for 6 h. The cleaved compound was analyzed by LC-MS and the observed mass was consistent with structure. Mass m / z 1063.8 [M + 2H] + .
- the solid support bound compound 142 was synthesized using solid phase peptide synthesis methods.
- the solid support bound compound 143 was synthesized using standard solid phase synthesis on a DNA synthesizer.
- the solid support bound compound 143 was suspended in aqueous ammonia (28-30 wt%) and heated at 55 °C for 16 h. The solution was cooled and the solid support was filtered. The filtrate was concentrated and the residue dissolved in water and purified by HPLC on a strong anion exchange column. The fractions containing full length compound 144 were pooled together and desalted. The resulting GalNAc 4 -11 conjugated oligomeric compound was analyzed by LC-MS and the observed mass was consistent with structure.
- the GalNAc 4 cluster portion of the conjugate group GalNAc 4 -11 (GalNAc 4 -11 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 4 -11 (GalNAc 4 -11 a -CM) is shown below:
- Oligomeric Compound 155 comprising a GalNAc 3 -6 conjugate group, was prepared using the general procedures illustrated in Example 46.
- the GalNAc 3 cluster portion of the conjugate group GalNAc 3 -6 (GalNAc 3 -6 a ) can be combined with any cleavable moiety to provide a variety of conjugate groups.
- GalNAc 3 -6 (GalNAc 3 -6 a -CM-) is shown below:
- Example 56 Dose-dependent study of oligonucleotides comprising either a 3' or 5'-conjugate group (comparison of GalNAc 3 -1, 2, 3, 5, 6, 7 and 10) targeting SRB-1 in vivo
- oligonucleotides listed below were tested in a dose-dependent study for antisense inhibition of SRB-1 in mice.
- Unconjugated ISIS 353382 was included as a standard.
- Each of the various GalNAc 3 conjugate groups was attached at the 5' terminus of the respective oligonucleotide by a phosphodiester linked 2'-deoxyadenosine nucleoside (cleavable moiety) except for ISIS 655861 which had the GalNAc 3 conjugate group attached at the 3' terminus.
- Table 42 Modified ASO targeting SRB-1 ASO Sequence (5' to 3') Motif Conjugate SEQ ID No.
- ISIS 353382 (parent) 5/10/5 no conjugate 108 ISIS 655861 5/10/5 GalNAc 3 -1 110 ISIS 664507 5/10/5 GalNAc 3 -2 109 ISIS 661161 5/10/5 GalNAc 3 -3 109 ISIS 666224 5/10/5 GalNAc 3 -5 109 ISIS 666961 5/10/5 GalNAc 3 -6 109 ISIS 666981 5/10/5 GalNAc 3 -7 109 ISIS 666881 5/10/5 GalNAc 3 -10 109
- GalNAc 3 -1 a was shown previously in Example 9.
- the structure of GalNAc 3 -2 a was shown previously in Example 37.
- the structure of GalNAc 3 -3 a was shown previously in Example 39.
- the structure of GalNAc 3 -5 a was shown previously in Example 49.
- the structure of GalNAc 3 -6 a was shown previously in Example 51.
- the structure of GalNAc 3 -7 a was shown previously in Example 48.
- the structure of GalNAc 3 -10 a was shown previously in Example 46.
- mice Six week old male Balb/c mice (Jackson Laboratory, Bar Harbor, ME) were injected subcutaneously once at the dosage shown below with ISIS 353382, 655861, 664507, 661161, 666224, 666961, 666981, 666881 or with saline. Each treatment group consisted of 4 animals. The mice were sacrificed 72 hours following the final administration to determine the liver SRB-1 mRNA levels using real-time PCR and RIBOGREEN® RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) according to standard protocols. The results below are presented as the average percent of SRB-1 mRNA levels for each treatment group, normalized to the saline control.
- ALT alanine aminotransferase
- AST aspartate aminotransferase
- oligonucleotides listed below were tested in a multiple dose study for antisense inhibition of SRB-1 in primary mouse hepatocytes.
- ISIS 353382 was included as an unconjugated standard.
- Each of the conjugate groups were attached at the 3' or 5' terminus of the respective oligonucleotide by a phosphodiester linked 2'-deoxyadenosine nucleoside cleavable moiety.
- Table 52 Modified ASO targeting SRB-1 ASO Sequence (5' to 3') Motif Conjugate SEQ ID No.
- GalNAc 3 -1 a was shown previously in Example 9.
- the structure of GalNAc 3 -3 a was shown previously in Example 39.
- the structure of GalNAc 3 -8a was shown previously in Example 47.
- the structure of GalNAc 3 -9a was shown previously in Example 52.
- the structure of GalNAc 3 -6 a was shown previously in Example 51.
- the structure of GalNAc 3 -2a was shown previously in Example 37.
- the structure of GalNAc 3 -10a was shown previously in Example 46.
- the structure of GalNAc 3 -5a was shown previously in Example 49.
- the structure of GalNAc 3 -7 a was shown previously in Example 48.
- oligonucleotides listed above were tested in vitro in primary mouse hepatocyte cells plated at a density of 25,000 cells per well and treated with 0.03, 0.08, 0.24, 0.74, 2.22, 6.67 or 20 nM modified oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and mRNA levels were measured by quantitative real-time PCR and the SRB-1 mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®.
- the IC 50 was calculated using standard methods and the results are presented in Table 53. The results show that, under free uptake conditions in which no reagents or electroporation techniques are used to artificially promote entry of the oligonucleotides into cells, the oligonucleotides comprising a GalNAc conjugate were significantly more potent in hepatocytes than the parent oligonucleotide (ISIS 353382) that does not comprise a GalNAc conjugate.
- Table 53 ASO IC 50 (nM) Internucleoside linkages Conjugate SEQ ID No.
- ISIS 353382 190 a PS none 108 ISIS 655861 11 a PS GalNAc 3 -1 110 ISIS 655862 3 PO/PS GalNAc 3 -1 110 ISIS 661161 15 a PS GalNAc 3 -3 109 ISIS 665001 20 PS GalNAc 3 -8 109 ISIS 664078 55 PS GalNAc 3 -9 110 ISIS 666961 22 a PS GalNAc 3 -6 109 ISIS 664507 30 PS GalNAc 3 -2 109 ISIS 666881 30 PS GalNAc 3 -10 109 ISIS 666224 30 a PS GalNAc 3 -5 109 ISIS 666981 40 PS GalNAc 3 -7 109 a Average of multiple runs.
- Example 79 Duration of action in vivo of oligonucleotides targeting APOC-III comprising a GalNAc 3 conjugate
- Table 70 Modified ASOs targeting APOC-III ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No.
- GalNAc 3 -1 a was shown previously in Example 9
- GalNAc 3 -3 a was shown in Example 39
- GalNAc 3 -7 a was shown in Example 48
- GalNAc 3 -10 a was shown in Example 46
- GalNAc 3 -13 a was shown in Example 62.
- mice Six to eight week old transgenic mice that express human APOC-III were each injected subcutaneously once with an oligonucleotide listed in Table 70 or with PBS. Each treatment group consisted of 3 animals. Blood was drawn before dosing to determine baseline and at 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, and 6 weeks following the dose. Plasma triglyceride and APOC-III protein levels were measured as described in Example 20.
- Example 80 Antisense inhibition in vivo by oligonucleotides targeting Alpha-1 Antitrypsin (A1AT) comprising a GalNAc 3 Conjugate
- oligonucleotides listed in Table 72 below were tested in a study for dose-dependent inhibition of A1AT in mice.
- Table 72 Modified ASOs targeting A1AT ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No.
- GalNAc 3 -1 a was shown previously in Example 9
- GalNAc 3 -3 a was shown in Example 39
- GalNAc 3 -7 a was shown in Example 48
- GalNAc 3 -10 a was shown in Example 46
- GalNAc 3 -13 a was shown in Example 62.
- mice Six week old, male C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were each injected subcutaneously once per week at a dosage shown below, for a total of three doses, with an oligonucleotide listed in Table 72 or with PBS. Each treatment group consisted of 4 animals. The mice were sacrificed 72 hours following the final administration. A1AT liver mRNA levels were determined using real-time PCR and RIBOGREEN® RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) according to standard protocols. A1AT plasma protein levels were determined using the Mouse Alpha 1-Antitrypsin ELISA (catalog # 41-A1AMS-E01, Alpco, Salem, NH). The results below are presented as the average percent of A1AT liver mRNA and plasma protein levels for each treatment group, normalized to the PBS control.
- A1AT liver mRNA % PBS
- A1AT plasma protein % PBS
- GalNAc 3 Cluster CM PBS n/a 100 100 n/a n/a 476366 5 86 78 n/a n/a 15 73 61 45 30 38 656326 0.6 99 90 GalNAc 3 -1a A d 2 61 70 6 15 30 18 6 10 678381 0.6 105 90 GalNAc 3 -3a A d 2 53 60 6 16 20 18 7 13 678382 0.6 90 79 GalNAc 3 -7a A d 2 49 57 6 21 27 18 8 11 678383 0.6 94 84 GalNAc 3 -10a A d 2 44 53 6 13 24 18 6 10 678384 0.6 106 91 GalNAc 3 -13a A d 2 65 59 6 26 31 18 11 15
- Liver transaminase and BUN levels in plasma were measured at time of sacrifice using standard protocols. Body weights and organ weights were also measured. The results are shown in Table 74 below. Body weight is shown as % relative to baseline. Organ weights are shown as % of body weight relative to the PBS control group. Table 74 ISIS No.
- Example 81 Duration of action in vivo of oligonucleotides targeting A1AT comprising a GalNAc 3 cluster
- oligonucleotides listed in Table 72 were tested in a single dose study for duration of action in mice.
- mice Six week old, male C57BL/6 mice were each injected subcutaneously once with an oligonucleotide listed in Table 72 or with PBS. Each treatment group consisted of 4 animals. Blood was drawn the day before dosing to determine baseline and at 5, 12, 19, and 25 days following the dose. Plasma A1AT protein levels were measured via ELISA (see Example 80). The results below are presented as the average percent of plasma A1AT protein levels for each treatment group, normalized to baseline levels. The results show that the oligonucleotides comprising a GalNAc conjugate were more potent and had longer duration of action than the parent lacking a GalNAc conjugate (ISIS 476366).
- oligonucleotides comprising a 5'-GalNAc conjugate (ISIS 678381, 678382, 678383, and 678384) were generally even more potent with even longer duration of action than the oligonucleotide comprising a 3'-GalNAc conjugate (ISIS 656326).
- Table 75 Plasma A1AT protein levels in mice ISIS No.
- GalNAc 3 Cluster CM PBS n/a 5 93 n/a n/a 12 93 19 90 25 97 476366 100 5 38 n/a n/a 12 46 19 62 25 77 656326 18 5 33 GalNAc 3 -1a A d 12 36 19 51 25 72 678381 18 5 21 GalNAc 3 -3a A d 12 21 19 35 25 48 678382 18 5 21 GalNAc 3 -7a A d 12 21 19 39 25 60 678383 18 5 24 GalNAc 3 -10a A d 12 21 19 45 25 73 678384 18 5 29 GalNAc 3 -13a A d 12 34 19 57 25 76
- Example 82 Antisense inhibition in vitro by oligonucleotides targeting SRB-1 comprising a GalNAc 3 conjugate
- Example 83 Antisense inhibition in vivo by oligonucleotides targeting Factor XI comprising a GalNAc 3 cluster
- oligonucleotides listed in Table 77 below were tested in a study for dose-dependent inhibition of Factor XI in mice.
- Table 77 Modified oligonucleotides targeting Factor XI ISIS No. Sequence (5' to 3') GalNAc cluster CM SEQ ID No.
- GalNAc 3 -1 a was shown previously in Example 9
- GalNAc 3 -3 a was shown in Example 39
- GalNAc 3 -7 a was shown in Example 48
- GalNAc 3 -10 a was shown in Example 46
- GalNAc 3 -13 a was shown in Example 62.
- mice Six to eight week old mice were each injected subcutaneously once per week at a dosage shown below, for a total of three doses, with an oligonucleotide listed below or with PBS. Each treatment group consisted of 4 animals. The mice were sacrificed 72 hours following the final dose. Factor XI liver mRNA levels were measured using real-time PCR and normalized to cyclophilin according to standard protocols. Liver transaminases, BUN, and bilirubin were also measured. The results below are presented as the average percent for each treatment group, normalized to the PBS control.
- Example 84 Duration of action in vivo of oligonucleotides targeting Factor XI comprising a GalNAc 3 Conjugate
- oligonucleotides listed in Table 77 were tested in a single dose study for duration of action in mice.
- mice Six to eight week old mice were each injected subcutaneously once with an oligonucleotide listed in Table 77 or with PBS. Each treatment group consisted of 4 animals. Blood was drawn by tail bleeds the day before dosing to determine baseline and at 3, 10, and 17 days following the dose. Plasma Factor XI protein levels were measured by ELISA using Factor XI capture and biotinylated detection antibodies from R & D Systems, Minneapolis, MN (catalog # AF2460 and # BAF2460, respectively) and the OptEIA Reagent Set B (Catalog # 550534, BD Biosciences, San Jose, CA). The results below are presented as the average percent of plasma Factor XI protein levels for each treatment group, normalized to baseline levels.
- GalNAc 3 Cluster CM SEQ ID No. PBS n/a 3 123 n/a n/a n/a 10 56 17 100 404071 30 3 11 n/a n/a 115 10 47 17 52 656173 6 3 1 GalNAc 3 -1a A d 113 10 3 17 21 663086 6 3 1 GalNAc 3 -3a A d 124 10 2 17 9 678347 6 3 1 GalNAc 3 -7a A d 124 10 1 17 8 678348 6 3 1 GalNAc 3 -10a A d 124 10 1 17 6 678349 6 3 1 GalNAc 3 -13a A d 124 10 1 17 5
- Example 85 Antisense inhibition in vivo by oligonucleotides targeting SRB-1 comprising a GalNAc 3 Conjugate
- Oligonucleotides listed in Table 76 were tested in a dose-dependent study for antisense inhibition of SRB-1 in mice.
- mice Six to eight week old C57BL/6 mice were each injected subcutaneously once per week at a dosage shown below, for a total of three doses, with an oligonucleotide listed in Table 76 or with saline. Each treatment group consisted of 4 animals. The mice were sacrificed 48 hours following the final administration to determine the SRB-1 mRNA levels using real-time PCR and RIBOGREEN® RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) according to standard protocols. The results below are presented as the average percent of liver SRB-1 mRNA levels for each treatment group, normalized to the saline control.
- Table 80 SRB-1 mRNA in liver ISIS No. Dosage (mg/kg) SRB-1 mRNA (% Saline) GalNAc 3 Cluster CM Saline n/a 100 n/a n/a 655861 0.1 94 GalNAc 3 -1a A d 0.3 119 1 68 3 32 661161 0.1 120 GalNAc 3 -3a A d 0.3 107 1 68 3 26 666881 0.1 107 GalNAc 3 -10a A d 0.3 107 1 69 3 27 666981 0.1 120 GalNAc 3 -7a A d 0.3 103 1 54 3 21 670061 0.1 118 GalNAc 3 -13a A d 0.3 89 1 52 3 18 677842 0.1 119 GalNAc 3 -20a A d 0.3 96 1 65 3 23 Table 81 SRB-1 mRNA in liver ISIS No. Dosage (mg/kg) SRB-1 mRNA (% Saline) GalNAc 3 Cluster CM Sa
- Example 86 Antisense inhibition in vivo by oligonucleotides targeting TTR comprising a GalNAc 3 cluster
- Oligonucleotides listed in Table 83 below were tested in a dose-dependent study for antisense inhibition of human transthyretin (TTR) in transgenic mice that express the human TTR gene.
- TTR transgenic mice Eight week old TTR transgenic mice were each injected subcutaneously once per week for three weeks, for a total of three doses, with an oligonucleotide and dosage listed in the tables below or with PBS. Each treatment group consisted of 4 animals. The mice were sacrificed 72 hours following the final administration. Tail bleeds were performed at various time points throughout the experiment, and plasma TTR protein, ALT, and AST levels were measured and reported in Tables 85-87. After the animals were sacrificed, plasma ALT, AST, and human TTR levels were measured, as were body weights, organ weights, and liver human TTR mRNA levels. TTR protein levels were measured using a clinical analyzer (AU480, Beckman Coulter, CA).
- RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) were used according to standard protocols to determine liver human TTR mRNA levels.
- the results presented in Tables 84-87 are the average values for each treatment group.
- the mRNA levels are the average values relative to the average for the PBS group.
- Plasma protein levels are the average values relative to the average value for the PBS group at baseline.
- Body weights are the average percent weight change from baseline until sacrifice for each individual treatment group. Organ weights shown are normalized to the animal's body weight, and the average normalized organ weight for each treatment group is then presented relative to the average normalized organ weight for the PBS group.
- BL indicates baseline, measurements that were taken just prior to the first dose.
- treatment with antisense oligonucleotides lowered TTR expression levels in a dose-dependent manner.
- the oligonucleotides comprising a GalNAc conjugate were more potent than the parent lacking a GalNAc conjugate (ISIS 420915).
- the oligonucleotides comprising a GalNAc conjugate and mixed PS/PO internucleoside linkages were even more potent than the oligonucleotide comprising a GalNAc conjugate and full PS linkages.
- Table 83 Oligonucleotides targeting human TTR Isis No.
- the structure of GalNAc 3 -7 a was shown in Example 48.
- the structure of GalNAc 3 -10 a was shown in Example 46.
- the structure of GalNAc 3 -13 a was shown in Example 62.
- the structure of GalNAc 3 -19 a was shown in Example 70.
- Table 84 Antisense inhibition of human TTR in vivo Isis No. Dosage (mg/kg) TTR mRNA (% PBS) Plasma TTR protein (%PBS) GalNAc cluster CM SEQ ID No.
- Example 88 Splicing modulation in vivo by oligonucleotides targeting SMN comprising a GalNAc 3 conjugate
- oligonucleotides listed in Table 90 were tested for splicing modulation of human survival of motor neuron (SMN) in mice.
- SSN motor neuron
- Table 90 Modified ASOs targeting SMN ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No.
- GalNAc 3 -7 a 387954 n/a n/a 126 699819 GalNAc 3 -7a PO 126 699821 GalNAc 3 -7a PO 126 700000 GalNAc 3 -1a
- the structure of GalNAc 3 -7 a was shown previously in Example 48.
- ISIS numbers 703421 and 703422 are morphlino oligonucleotides, wherein each nucleotide of the two oligonucleotides is a morpholino nucleotide.
- mice that express human SMN were injected subcutaneously once with an oligonucleotide listed in Table 91 or with saline. Each treatment group consisted of 2 males and 2 females. The mice were sacrificed 3 days following the dose to determine the liver human SMN mRNA levels both with and without exon 7 using real-time PCR according to standard protocols. Total RNA was measured using Ribogreen reagent. The SMN mRNA levels were normalized to total mRNA, and further normalized to the averages for the saline treatment group. The resulting average ratios of SMN mRNA including exon 7 to SMN mRNA missing exon 7 are shown in Table 91.
- Example 89 Antisense inhibition in vivo by oligonucleotides targeting Apolipoprotein A (Apo(a)) comprising a GalNAc 3 conjugate
- oligonucleotides listed in Table 92 below were tested in a study for dose-dependent inhibition of Apo(a) in transgenic mice.
- Table 92 Modified ASOs targeting Apo(a) ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No. 494372 n/a n/a 25 681257 GalNAc 3 -7a PO 25
- the structure of GalNAc 3 -7 a was shown in Example 48.
- mice Eight week old, female C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were each injected subcutaneously once per week at a dosage shown below, for a total of six doses, with an oligonucleotide listed in Table 92 or with PBS. Each treatment group consisted of 3-4 animals. Tail bleeds were performed the day before the first dose and weekly following each dose to determine plasma Apo(a) protein levels. The mice were sacrificed two days following the final administration. Apo(a) liver mRNA levels were determined using real-time PCR and RIBOGREEN® RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) according to standard protocols.
- Apo(a) plasma protein levels were determined using ELISA, and liver transaminase levels were determined.
- the mRNA and plasma protein results in Table 93 are presented as the treatment group average percent relative to the PBS treated group. Plasma protein levels were further normalized to the baseline (BL) value for the PBS group. Average absolute transaminase levels and body weights (% relative to baseline averages) are reported in Table 94.
- Example 90 Antisense inhibition in vivo by oligonucleotides targeting TTR comprising a GalNAc 3 cluster
- Oligonucleotides listed in Table 95 below were tested in a dose-dependent study for antisense inhibition of human transthyretin (TTR) in transgenic mice that express the human TTR gene.
- TTR transgenic mice were each injected subcutaneously once per week for three weeks, for a total of three doses, with an oligonucleotide and dosage listed in Table 96 or with PBS. Each treatment group consisted of 4 animals. Prior to the first dose, a tail bleed was performed to determine plasma TTR protein levels at baseline (BL). The mice were sacrificed 72 hours following the final administration. TTR protein levels were measured using a clinical analyzer (AU480, Beckman Coulter, CA). Real-time PCR and RIBOGREEN® RNA quantification reagent (Molecular Probes, Inc. Eugene, OR) were used according to standard protocols to determine liver human TTR mRNA levels. The results presented in Table 96 are the average values for each treatment group.
- the mRNA levels are the average values relative to the average for the PBS group.
- Plasma protein levels are the average values relative to the average value for the PBS group at baseline. "BL” indicates baseline, measurements that were taken just prior to the first dose. As illustrated in Table 96, treatment with antisense oligonucleotides lowered TTR expression levels in a dose-dependent manner.
- oligonucleotides comprising a GalNAc conjugate were more potent than the parent lacking a GalNAc conjugate (ISIS 420915), and oligonucleotides comprising a phosphodiester or deoxyadenosine cleavable moiety showed significant improvements in potency compared to the parent lacking a conjugate (see ISIS numbers 682883 and 666943 vs 420915 and see Examples 86 and 87).
- Table 95 Oligonucleotides targeting human TTR Isis No. Sequence 5' to 3' Linkages GalNAc cluster CM SEQ ID No.
- Example 74 The structure of GalNAc 3 -3 a was shown in Example 39.
- Example 92 Antisense inhibition in primary hepatocytes by antisense oligonucleotides targeting Apo-CIII comprising a GalNAc 3 conjugate
- Example 93 Antisense inhibition in vivo by oligonucleotides targeting SRB-1 comprising mixed wings and a 5'-GalNAc 3 conjugate
- Table 100 Modified ASOs targeting SRB-1 ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No.
- mice Six to eight week old C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were injected subcutaneously once at the dosage shown below with an oligonucleotide listed in Table 100 or with saline. Each treatment group consisted of 4 animals. The mice were sacrificed 72 hours following the final administration. Liver SRB-1 mRNA levels were measured using real-time PCR. SRB-1 mRNA levels were normalized to cyclophilin mRNA levels according to standard protocols. The results are presented as the average percent of SRB-1 mRNA levels for each treatment group relative to the saline control group.
- Body weights, liver transaminases, total bilirubin, and BUN were also measured, and the average values for each treatment group are shown in Table 101. Body weight is shown as the average percent body weight relative to the baseline body weight (% BL) measured just prior to the oligonucleotide dose. Table 101 SRB-1 mRNA, ALT, AST, BUN, and total bilirubin levels and body weights ISIS No.
- Example 94 Antisense inhibition in vivo by oligonucleotides targeting SRB-1 comprising 2'-sugar modifications and a 5'-GalNAc 3 conjugate
- Table 102 Modified ASOs targeting SRB-1 ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No. 353382 n/a n/a 108 700989 n/a n/a 133 666904 GalNAc 3 -3a PO 108 700991 GalNAc 3 -7a PO 133 Subscript "m" indicates a 2'-O-methyl modified nucleoside. See Example 74 for complete table legend. The structure of GalNAc 3 -3 a was shown previously in Example 39, and the structure of GalNAc 3 -7a was shown previously in Example 48.
- Example 95 Antisense inhibition in vivo by oligonucleotides targeting SRB-1 comprising bicyclic nucleosides and a 5'-GalNAc 3 conjugate
- Table 104 Modified ASOs targeting SRB-1 ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No 440762 T ks m C ks A ds G ds T ds m C ds A ds T ds G ds A ds m C ds T ks m C k n/a n/a 104 666905 GalNAc 3 -3 a - o' T ks m C ks A ds G ds T ds m C ds A ds T ds G ds A ds m C ds T ks T ks m C k GalNAc 3 -3 a PO 104 699782 GalNAc 3 -7 a - o'
- Example 74 table legend for other abbreviations.
- the structure of GalNAc 3 -1 a was shown previously in Example 9
- the structure of GalNAc 3 -3 a was shown previously in Example 39
- the structure of GalNAc 3 -7a was shown previously in Example 48.
- Example 96 Plasma protein binding of antisense oligonucleotides comprising a GalNAc 3 conjugate group
- Oligonucleotides listed in Table 70 targeting ApoC-III and oligonucleotides in Table 106 targeting Apo(a) were tested in an ultra-filtration assay in order to assess plasma protein binding.
- Table 106 Modified oligonucleotides targeting Apo(a) ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No 494372 n/a n/a 25 693401 n/a n/a 25 681251 GalNAc 3 -7 a PO 25 681257 GalNAc 3 -7 a PO 25 See the Example 74 for table legend. The structure of GalNAc 3 -7a was shown previously in Example 48.
- Ultrafree-MC ultrafiltration units (30,000 NMWL, low-binding regenerated cellulose membrane, Millipore, Bedford, MA) were pre-conditioned with 300 ⁇ L of 0.5% Tween 80 and centrifuged at 2000 g for 10 minutes, then with 300 ⁇ L of a 300 ⁇ g/mL solution of a control oligonucleotide in H 2 O and centrifuged at 2000 g for 16 minutes.
- the test oligonucleotides were added to 1.2 mL aliquots of plasma at two concentrations (5 and 150 ⁇ g/mL).
- An aliquot (300 ⁇ L) of each spiked plasma sample was placed in a pre-conditioned filter unit and incubated at 37°C for 30 minutes, immediately followed by centrifugation at 2000 g for 16 minutes.
- the average concentration of the filtered sample relative to the concentration of the unfiltered sample is used to determine the percent of oligonucleotide in the plasma that is not bound to plasma proteins (% unbound).
- the final unbound oligonucleotide values are corrected for non-specific binding by dividing the % unbound by the % recovery for each oligonucleotide.
- the final % bound oligonucleotide values are determined by subtracting the final % unbound values from 100. The results are shown in Table 107 for the two concentrations of oligonucleotide tested (5 and 150 ⁇ g/mL) in each species of plasma.
- Example 97 Modified oligonucleotides targeting TTR comprising a GalNAc 3 conjugate group
- the oligonucleotides shown in Table 108 comprising a GalNAc conjugate were designed to target TTR.
- the legend for Table 108 can be found in Example 74.
- GalNAc 3 -1 The structure of GalNAc 3 -1 was shown in Example 9.
- the structure of GalNAc 3 -3 a was shown in Example 39.
- the structure of GalNAc 3 -7 a was shown in Example 48.
- the structure of GalNAc 3 -10 a was shown in Example 46.
- the structure of GalNAc 3 -13 a was shown in Example 62.
- the structure of GalNAc 3 -19 a was shown in Example 70.
- GalNAc conjugate group did not have a significant effect in this assay.
- Example 99 Binding affinities of oligonucleotides comprising a GalNAc conjugate for the asialoglycoprotein receptor
- the binding affinities of the oligonucleotides listed in Table 110 were tested in a competitive receptor binding assay.
- the competitor ligand, ⁇ 1-acid glycoprotein (AGP) was incubated in 50 mM sodium acetate buffer (pH 5) with 1 U neuraminidase-agarose for 16 hours at 37°C, and > 90% desialylation was confirmed by either sialic acid assay or size exclusion chromatography (SEC).
- Iodine monochloride was used to iodinate the AGP according to the procedure by Atsma et al. (see J Lipid Res.
- de-AGP desialylated ⁇ 1-acid glycoprotein
- Cells were incubated for 30 min @37°C with 1ml competition mix containing appropriate growth media with 2% FBS, 10 -8 M 125 I - labeled de-AGP and GalNAc-cluster containing ASOs at concentrations ranging from 10 -11 to 10 -5 M. Non-specific binding was determined in the presence of 10 -2 M GalNAc sugar. Cells were washed twice with media without FBS to remove unbound 125 I -labeled de-AGP and competitor GalNAc ASO. Cells were lysed using Qiagen's RLT buffer containing 1% ⁇ -mercaptoethanol. Lysates were transferred to round bottom assay tubes after a brief 10 min freeze/thaw cycle and assayed on a ⁇ -counter.
- Non-specific binding was subtracted before dividing 125 I protein counts by the value of the lowest GalNAc-ASO concentration counts.
- the inhibition curves were fitted according to a single site competition binding equation using a nonlinear regression algorithm to calculate the binding affinities (K D 's).
- Table 110 Asialoglycoprotein receptor binding assay results ISIS No.
- GalNAc conjugate Oligonucleotide end to which GalNAc conjugate is attached K D (nM) 661161 a GalNAc 3 -3 5' 3.7 666881 a GalNAc 3 -10 5' 7.6 666981 GalNAc 3 -7 5' 6.0 670061 GalNAc 3 -13 5' 7.4 655861 a GalNAc 3 -1 3' 11.6 677841 3 GalNAc 3 -19 3' 60.8
- Example 100 Antisense inhibition in vivo by oligonucleotides comprising a GalNAc conjugate group targeting Apo(a) in vivo
- Table 111a Modified ASOs targeting APO(a) ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No. 681251 GalNAc 3 -7a PO 25 681257 GalNAc 3 -7a PO 25 The structure of GalNAc 3 -7 a was shown in Example 48.
- mice that express human Apo(a) were each injected subcutaneously once per week, for a total of 6 doses, with an oligonucleotide and dosage listed in Table 111b or with PBS. Each treatment group consisted of 3 animals. Blood was drawn the day before dosing to determine baseline levels of Apo(a) protein in plasma and at 72 hours, 1 week, and 2 weeks following the first dose. Additional blood draws will occur at 3 weeks, 4 weeks, 5 weeks, and 6 weeks following the first dose. Plasma Apo(a) protein levels were measured using an ELISA.
- Table 111b The results in Table 111b are presented as the average percent of plasma Apo(a) protein levels for each treatment group, normalized to baseline levels (% BL), The results show that the oligonucleotides comprising a GalNAc conjugate group exhibited potent reduction in Apo(a) expression. This potent effect was observed for the oligonucleotide that comprises full PS internucleoside linkages and the oligonucleotide that comprises mixed PO and PS linkages. Table 111b Apo(a) plasma protein levels ISIS No.
- Example 101 Antisense inhibition by oligonucleotides comprising a GalNAc cluster linked via a stable moiety
- the oligonucleotides listed in Table 112 were tested for inhibition of mouse APOC-III expression in vivo.
- C57B1/6 mice were each injected subcutaneously once with an oligonucleotide listed in Table 112 or with PBS.
- Each treatment group consisted of 4 animals.
- Each mouse treated with ISIS 440670 received a dose of 2, 6, 20, or 60 mg/kg.
- Each mouse treated with ISIS 680772 or 696847 received 0.6, 2, 6, or 20 mg/kg.
- the GalNAc conjugate group of ISIS 696847 is linked via a stable moiety, a phosphorothioate linkage instead of a readily cleavable phosphodiester containing linkage. The animals were sacrificed 72 hours after the dose.
- Liver APOC-III mRNA levels were measured using real-time PCR. APOC-III mRNA levels were normalized to cyclophilin mRNA levels according to standard protocols. The results are presented in Table 112 as the average percent of APOC-III mRNA levels for each treatment group relative to the saline control group. The results show that the oligonucleotides comprising a GalNAc conjugate group were significantly more potent than the oligonucleotide lacking a conjugate group.
- oligonucleotide comprising a GalNAc conjugate group linked to the oligonucleotide via a cleavable moiety (ISIS 680772) was even more potent than the oligonucleotide comprising a GalNAc conjugate group linked to the oligonucleotide via a stable moiety (ISIS 696847).
- Table 112 Modified oligonucleotides targeting mouse APOC-III ISIS No. Sequences (5' to 3') CM Dosage (mg/kg) APOC-III mRNA (% PBS) SEQ ID No.
- Example 108 Antisense inhibition in vivo by oligonucleotides comprising a GalNAc conjugate group targeting Apo(a) in vivo
- the oligonucleotides listed in Table 118 below were tested in a single dose study in mice.
- Table 118 Modified ASOs targeting APO(a) ISIS No. Sequences (5' to 3') GalNAc 3 Cluster CM SEQ ID No. 494372 n/a n/a 25 681251 GalNAc 3 -7a PO 25 681255 GalNAc 3 -3 a PO 25 681256 GalNAc 3 -10a PO 25 681257 GalNAc 3 -7a PO 25 681258 GalNAc 3 -13a PO 25 681260 GalNAc 3 -19a
- a d 134 The structure of GalNAc 3 -7 a was shown in Example 48.
- mice that express human Apo(a) were each injected subcutaneously once with an oligonucleotide and dosage listed in Table 119 or with PBS. Each treatment group consisted of 4 animals. Blood was drawn the day before dosing to determine baseline levels of Apo(a) protein in plasma and at 1 week following the first dose. Additional blood draws will occur weekly for approximately 8 weeks. Plasma Apo(a) protein levels were measured using an ELISA. The results in Table 119 are presented as the average percent of plasma Apo(a) protein levels for each treatment group, normalized to baseline levels (% BL), The results show that the antisense oligonucleotides reduced Apo(a) protein expression.
- oligonucleotides comprising a GalNAc conjugate group exhibited even more potent reduction in Apo(a) expression than the oligonucleotide that does not comprise a conjugate group.
- Table 119 Apo(a) plasma protein levels ISIS No. Dosage (mg/kg) Apo(a) at 1 week (% BL) PBS n/a 143 494372 50 58 681251 10 15 681255 10 14 681256 10 17 681257 10 24 681258 10 22 681260 10 26
- Example 111 Synthesis of oligonucleotides comprising a GalNAc 2 -31 or GalNAc 2 -32 conjugate
- Oligonucleotide 250 comprising a GalNAc 2 -31 conjugate group, wherein Y is selected from O, S, a substituted or unsubstituted C 1 -C 10 alkyl, amino, substituted amino, azido, alkenyl or alkynyl, is synthesized as shown above.
- the GalNAc 2 cluster portion (GalNAc 2 -31 a ) of the conjugate group GalNAc 2 -31 can be combined with any cleavable moiety to provide a variety of conjugate groups.
- the Y-containing group directly adjacent to the 5'-end of the oligonucleotide is part of the cleavable moiety.
- the Y-containing group directly adjacent to the 5'-end of the oligonucleotide is part of a stable moiety, and the cleavable moiety is present on the oligonucleotide.
- the structure of GalNAc 2 -31 a is shown below:
- Oligonucleotide 252 comprising a GalNAc 2 -32 conjugate group, wherein Y is selected from O, S, a substituted or unsubstituted C 1 -C 10 alkyl, amino, substituted amino, azido, alkenyl or alkynyl, is synthesized as shown above.
- the GalNAc 2 cluster portion (GalNAc 2 -32 a ) of the conjugate group GalNAc 2 -32 can be combined with any cleavable moiety to provide a variety of conjugate groups.
- the Y-containing group directly adjacent to the 5'-end of the oligonucleotide is part of the cleavable moiety.
- the Y-containing group directly adjacent to the 5'-end of the oligonucleotide is part of a stable moiety, and the cleavable moiety is present on the oligonucleotide.
- the structure of GalNAc 2 -32 a is shown below:
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Claims (15)
- Composé selon la revendication 1, dans lequel le lieur comprend une aminé, un amide, un ester, un éther, une pyrrolidine, un PEG, un polyamide ou une liaison disulfure.
- Composé selon la revendication 1 ou 2, dans lequel le lieur ne comprend pas une pyrrolidine.
- Composé selon l'une quelconque des revendications 1 ou 2, dans lequel le lieur a la formule :CM est un fragment clivable et T3 est un nucléoside, un nucléotide, une sous-unité monomère ou un composé oligomère ;
- Composé selon l'une quelconque des revendications 1 à 4, dans lequel T2 ou T3 est un groupe comprenant un composé oligomère, et dans lequel le composé oligomère est un oligonucléotide modifié ;
par exemple, dans lequel l'oligonucléotide modifié est constitué de 10 à 30 nucléosides liés, dans lequel au moins un nucléoside est un nucléoside modifié ;
par exemple, dans lequel l'oligonucléotide modifié comprend au moins un nucléoside modifié choisi parmi : un 2'-MOE-nucléoside, un 2'-OMe-nucléoside, un 2'-F-nucléoside, un (4'-CH2-O-2')-nucléoside bicyclique, un (4'-(CH2)2-O-2')-nucléoside bicyclique, un (4'-C(CH3)H-O-2')-nucléoside bicyclique ; et un morpholino. - Composé selon la revendication 5, dans lequel l'oligonucléotide modifié comporte un motif de gapmer-sucre comprenant :une région en 5' constituée de 2 à 8 nucléosides de région en 5' liés, dans lequel au moins deux nucléosides de région en 5' sont des nucléosides modifiés et dans lequel le nucléoside le plus en 3' de la région en 5' est un nucléoside modifié ;une région en 3' constituée de 2 à 8 nucléosides de région en 3' liés, dans lequel au moins deux nucléosides de région en 3' sont des nucléosides modifiés et dans lequel le nucléoside le plus en 5' de la région en 3' est un nucléoside modifié ; etune région centrale entre la région en 5' et la région en 3' constituée de 5 à 10 nucléosides de région centrale liés, chacun indépendamment choisi parmi : un nucléoside modifié et un désoxynucléoside non modifié, dans lequel le nucléoside le plus en 5' de région centrale est un désoxynucléoside non modifié et le nucléoside le plus en 3' de région centrale est un désoxynucléoside non modifié ;facultativement dans lequel chaque nucléoside de région en 5' est un nucléoside modifié ; chaque nucléoside de région en 3' est un nucléoside modifié ; et chaque nucléoside de région centrale est un désoxynucléoside non modifié.
- Composé selon la revendication 6, dans lequel la région en 5' est constituée de 2 à 5 nucléosides de région en 5' liés ; la région en 3' est constitué de 2 à 5 nucléosides de région en 3' liés ; et la région centrale est constituée de 8 à 10 nucléosides de région centrale.
- Composé selon l'une quelconque des revendications 5 à 7, dans lequel l'oligonucléotide modifié comprend au moins une liaison internucléosidique phosphorothioate ;
et/ou, dans lequel l'oligonucléotide modifié comprend au moins une liaison internucléosidique phosphodiester ; et/ou, dans lequel chaque liaison internucléosidique de l'oligonucléotide modifié est une liaison internucléosidique phosphorothioate ou une liaison internucléosidique phosphodiester. - Composé selon l'une quelconque des revendications 5 à 8, dans lequel l'oligonucléotide modifié est lié au reste du composé à l'extrémité 5' de l'oligonucléotide modifié ;
ou dans lequel l'oligonucléotide modifié est lié au reste du composé à l'extrémité 3' de l'oligonucléotide modifié. - Composé selon l'une quelconque des revendications 5 à 9, dans lequel l'oligonucléotide modifié est un oligonucléotide antisens.
- Composé selon l'une quelconque des revendications 5 à 10, dans lequel l'oligonucléotide modifié est simple brin ou dans lequel l'oligonucléotide modifié est double brin.
- Composé selon l'une quelconque des revendications 5 à 11, dans lequel l'oligonucléotide modifié active la voie RISC ;
ou dans lequel l'oligonucléotide modifié est un composé antisens à base de RNase H
ou dans lequel l'oligonucléotide modifié modifie l'épissage d'un pré-ARNm cible. - Composé selon l'une quelconque des revendications 10 à 12, dans lequel l'oligonucléotide modifié est complémentaire d'un acide nucléique cible ; par exemple
dans lequel l'acide nucléique cible est choisi parmi :
un pré-ARNm, un microARN, ou un ARN non codant long. - Composé selon l'une quelconque des revendications 10 à 13, dans lequel l' oligonucléotide modifié est constitué de 10 à 30 nucléosides liés ;
par exemple, dans lequel l'oligonucléotide modifié est constitué de 18 à 22 nucléosides liés ;
par exemple, dans lequel l'oligonucléotide modifié est constitué de 16 à 20 nucléosides liés. - Composé selon les revendications 5 à 14 pour utilisation dans un procédé de traitement d'un trouble métabolique ou d'un trouble cardiovasculaire comprenant l'administration du composé selon l'une quelconque des revendications 5 à 14 à un sujet en ayant besoin.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11707528B2 (en) | 2020-07-01 | 2023-07-25 | Shenzhen Rhegen Biotechnology Co., Ltd. | Mannose-based mRNA targeted delivery system and use thereof |
US11759532B2 (en) | 2019-12-17 | 2023-09-19 | Shenzhen Rhegen Biotechnology Co., Ltd. | mRNA targeting molecule comprising N-acetylgalactosamine binding polypeptide and preparation method therefor |
Families Citing this family (434)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2966011C (fr) | 2008-10-15 | 2021-10-19 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression du facteur 11 |
BRPI0923225A2 (pt) | 2008-12-02 | 2016-10-04 | Chiralgen Ltd | metodo para sintese de acidos nucleicos modificados no atomo de fosforo |
RU2612521C2 (ru) | 2009-07-06 | 2017-03-09 | Онтории, Инк. | Новые пролекарства нуклеиновых кислот и способы их применения |
US10428019B2 (en) | 2010-09-24 | 2019-10-01 | Wave Life Sciences Ltd. | Chiral auxiliaries |
CA3077910A1 (fr) | 2010-11-17 | 2012-05-24 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression de l'alpha synucleine |
CN107365339A (zh) | 2011-07-19 | 2017-11-21 | 波涛生命科学有限公司 | 合成官能化核酸的方法 |
DK2751270T3 (en) | 2011-08-29 | 2018-10-29 | Ionis Pharmaceuticals Inc | OLIGOMER-CONJUGATE COMPLEXES AND THEIR USE |
US10273474B2 (en) | 2012-03-30 | 2019-04-30 | Washington University | Methods for modulating Tau expression for reducing seizure and modifying a neurodegenerative syndrome |
WO2013159108A2 (fr) * | 2012-04-20 | 2013-10-24 | Isis Pharmaceuticals, Inc. | Composés oligomères comprenant des nucléotides bicycliques et utilisations de ceux-ci |
US9574193B2 (en) | 2012-05-17 | 2017-02-21 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating apolipoprotein (a) expression |
US20160002624A1 (en) | 2012-05-17 | 2016-01-07 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide compositions |
PT2855500T (pt) * | 2012-05-24 | 2020-09-24 | Ionis Pharmaceuticals Inc | Métodos e composições para modular a expressão de apolipoproteína(a) |
JP6246121B2 (ja) | 2012-07-13 | 2017-12-13 | 株式会社新日本科学 | キラル核酸アジュバント |
EP2872485B1 (fr) | 2012-07-13 | 2020-12-16 | Wave Life Sciences Ltd. | Groupe auxiliaire asymétrique |
PL2872147T3 (pl) | 2012-07-13 | 2023-09-25 | Wave Life Sciences Ltd. | Sposób wytwarzania chiralnych oligonukleotydów |
BR112015010116A2 (pt) | 2012-11-15 | 2017-08-22 | Roche Innovation Ct Copenhagen As | COMPOSTOS CONJUGADOS ANTI-SENTIDO ANTI-ApoB |
EP2951305B1 (fr) * | 2013-01-30 | 2018-08-15 | F.Hoffmann-La Roche Ag | Conjugués glucidiques d'oligonucléotides d'acides nucléiques bloqués |
US9593333B2 (en) * | 2013-02-14 | 2017-03-14 | Ionis Pharmaceuticals, Inc. | Modulation of apolipoprotein C-III (ApoCIII) expression in lipoprotein lipase deficient (LPLD) populations |
TW201446791A (zh) | 2013-05-01 | 2014-12-16 | Regulus Therapeutics Inc | 用於調節mir-122之微小rna化合物及方法 |
MX2015015239A (es) * | 2013-05-01 | 2016-10-03 | Ionis Pharmaceuticals Inc | Composiciones y metodos. |
US9506030B2 (en) | 2013-05-01 | 2016-11-29 | Regulus Therapeutics Inc. | Compounds and methods for enhanced cellular uptake |
RS59986B1 (sr) | 2013-06-27 | 2020-03-31 | Roche Innovation Ct Copenhagen As | Antisens oligomeri i konjugati koji ciljno deluju na pcsk9 |
US10808246B2 (en) * | 2013-07-11 | 2020-10-20 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
EP3022176B8 (fr) | 2013-07-15 | 2019-12-25 | The Regents of the University of California | Analogues azacycliques de fty720 à structure contrainte |
TW202246503A (zh) | 2013-07-19 | 2022-12-01 | 美商百健Ma公司 | 用於調節τ蛋白表現之組合物 |
WO2015042447A1 (fr) | 2013-09-20 | 2015-03-26 | Isis Pharmaceuticals, Inc. | Nucléosides thérapeutiques ciblées et leur utilisation |
CA2925107A1 (fr) * | 2013-10-02 | 2015-04-09 | Alnylam Pharmaceuticals, Inc. | Compositions et methodes d'inhibition de l'expression du gene lect2 |
US11162096B2 (en) | 2013-10-14 | 2021-11-02 | Ionis Pharmaceuticals, Inc | Methods for modulating expression of C9ORF72 antisense transcript |
WO2015061536A1 (fr) | 2013-10-25 | 2015-04-30 | Regulus Therapeutics Inc. | Composés de microarn et procédés de modulation de l'activité de mir-21 |
CA2928349A1 (fr) * | 2013-11-14 | 2015-05-21 | Roche Innovation Center Copenhagen A/S | Composes conjugues antisens apob |
JP6482475B2 (ja) * | 2014-01-07 | 2019-03-13 | レナセラピューティクス株式会社 | アンチセンスオリゴヌクレオチド及び糖誘導体を含む二本鎖オリゴヌクレオチド |
JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
EP3095460A4 (fr) | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Adjuvant d'acide nucléique chiral ayant une activité anti-allergique, et agent anti-allergique |
WO2015108047A1 (fr) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | Adjuvant d'acide nucléique chiral possédant une activité d'induction d'immunité, et activateur d'induction d'immunité |
JP6382344B2 (ja) | 2014-01-16 | 2018-08-29 | ウェイブ ライフ サイエンシズ リミテッドWave Life Sciences Ltd. | キラルデザイン |
CN113057959B (zh) | 2014-02-11 | 2024-07-16 | 阿尔尼拉姆医药品有限公司 | 己酮糖激酶(KHK)iRNA组合物及其使用方法 |
CA2942340A1 (fr) | 2014-03-19 | 2015-09-24 | Ionis Pharmaceuticals, Inc. | Compositions permettant de moduler l'expression de l'ataxine 2 |
US10006027B2 (en) | 2014-03-19 | 2018-06-26 | Ionis Pharmaceuticals, Inc. | Methods for modulating Ataxin 2 expression |
KR20220077933A (ko) | 2014-04-01 | 2022-06-09 | 바이오젠 엠에이 인코포레이티드 | Sod-1 발현을 조절하기 위한 조성물 |
RS59182B1 (sr) | 2014-05-01 | 2019-10-31 | Ionis Pharmaceuticals Inc | Kompozicije i postupci za modulaciju ekspresije faktora b komplementa |
EP3811977A1 (fr) * | 2014-05-01 | 2021-04-28 | Ionis Pharmaceuticals, Inc. | Procédé de synthèse de grappes de conjugués réactifs |
CA2946003A1 (fr) | 2014-05-01 | 2015-11-05 | Ionis Pharmaceuticals, Inc. | Compositions et methodes de modulation de l'expression de l'angiopoietine de type 3 |
BR112016022855B1 (pt) | 2014-05-01 | 2022-08-02 | Ionis Pharmaceuticals, Inc | Compostos e composições para modular a expressão de pkk e seus usos |
EP3974534A1 (fr) | 2014-05-01 | 2022-03-30 | Ionis Pharmaceuticals, Inc. | Compositions et procédés pour moduler l'expression du récepteur de l'hormone de croissance |
GB201408623D0 (en) * | 2014-05-15 | 2014-07-02 | Santaris Pharma As | Oligomers and oligomer conjugates |
WO2015179724A1 (fr) | 2014-05-22 | 2015-11-26 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni produisant un effet sur l'angiotensinogène (agt) et leurs procédés d'utilisation |
GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
SG11201610877PA (en) | 2014-08-07 | 2017-02-27 | Regulus Therapeutics Inc | Targeting micrornas for metabolic disorders |
US10436802B2 (en) | 2014-09-12 | 2019-10-08 | Biogen Ma Inc. | Methods for treating spinal muscular atrophy |
US9976143B2 (en) | 2014-10-03 | 2018-05-22 | Cold Spring Harbor Laboratory | Targeted augmentation of nuclear gene output |
RU2017114156A (ru) | 2014-10-10 | 2018-11-15 | Ф. Хоффманн-Ля Рош Аг | N-ацетилгалактозаминовые (galnac) фосфорамитиды, их конъюгаты с нуклеиновыми кислотами и их применение |
WO2016061487A1 (fr) * | 2014-10-17 | 2016-04-21 | Alnylam Pharmaceuticals, Inc. | Agents polynucléotidiques de ciblage d'acide aminolévulinique synthase-1 (alas1) et utilisations de ceux-ci |
JOP20200092A1 (ar) | 2014-11-10 | 2017-06-16 | Alnylam Pharmaceuticals Inc | تركيبات iRNA لفيروس الكبد B (HBV) وطرق لاستخدامها |
CA2968114A1 (fr) | 2014-11-17 | 2016-05-26 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni d'apolipoproteine c3 (apoc3) et procedes d'utilisation de ces compositions |
US20170369872A1 (en) | 2014-12-18 | 2017-12-28 | Alnylam Pharmaceuticals, Inc. | Reversir tm compounds |
WO2016112132A1 (fr) | 2015-01-06 | 2016-07-14 | Ionis Pharmaceuticals, Inc. | Compositions destinées à moduler l'expression du transcrit antisens c9orf72 |
US10538763B2 (en) | 2015-01-16 | 2020-01-21 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulation of DUX4 |
WO2016130806A2 (fr) | 2015-02-13 | 2016-08-18 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni du gène codant pour la protéine 3 contenant un domaine phospholipase de type patatine (pnpla3) et leurs procédés d'utilisation |
AU2016217825B2 (en) * | 2015-02-15 | 2022-03-10 | Arcturus Therapeutics, Inc. | Acyl-amino-LNA and/or hydrocarbyl-amino-LNA oligonucleotides |
US11129844B2 (en) | 2015-03-03 | 2021-09-28 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulating MECP2 expression |
KR102539587B1 (ko) | 2015-04-03 | 2023-06-01 | 아이오니스 파마수티컬즈, 인코포레이티드 | Tmprss6 발현을 조절하기 위한 화합물 및 방법들 |
MX2017012610A (es) | 2015-04-08 | 2018-03-16 | Alnylam Pharmaceuticals Inc | Composiciones y metodos para inhibir la expresion del gen lect2. |
US10407678B2 (en) | 2015-04-16 | 2019-09-10 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
WO2016172734A1 (fr) | 2015-04-24 | 2016-10-27 | California Institute Of Technology | Réactivation de gènes du chromosome x |
WO2016205323A1 (fr) | 2015-06-18 | 2016-12-22 | Alnylam Pharmaceuticals, Inc. | Agents polynucléotidiques ciblant l'hydroxyacide oxydase (glycolate oxydase, hao1) et procédés d'utilisation de ceux-ci |
WO2016209862A1 (fr) | 2015-06-23 | 2016-12-29 | Alnylam Pharmaceuticals, Inc. | Compositions d'arndb contre un gène de glucokinase (gck) et leurs procédés d'utilisation |
US11414657B2 (en) | 2015-06-29 | 2022-08-16 | Ionis Pharmaceuticals, Inc. | Modified CRISPR RNA and modified single CRISPR RNA and uses thereof |
WO2017011286A1 (fr) | 2015-07-10 | 2017-01-19 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de la sous-unité acide labile de la protéine se liant au facteur de croissance apparenté a l'insuline (igfals) et du facteur de croissance 1 apparenté a l'insuline (igf-1) et leurs procédés d'utilisation |
DK3320094T3 (da) | 2015-07-10 | 2022-05-23 | Ionis Pharmaceuticals Inc | Modulatorer af diacyglycerol-acyltransferase 2 (dgat2) |
US20180193471A1 (en) * | 2015-07-16 | 2018-07-12 | Kyowa Hakko Kirin Co., Ltd. | ß2GPI GENE EXPRESSION-SUPPRESSING NUCLEIC ACID CONJUGATE |
MA43072A (fr) * | 2015-07-22 | 2018-05-30 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
AU2016302697B2 (en) | 2015-08-06 | 2020-10-29 | F. Hoffmann-La Roche Ag | Processes for the preparation of GalNAc acid derivatives |
WO2017030973A1 (fr) | 2015-08-14 | 2017-02-23 | University Of Massachusetts | Conjugués bioactifs pour l'administration d'oligonucléotides |
CN105111119B (zh) * | 2015-08-14 | 2017-04-12 | 天津小新医药科技有限公司 | 一类卤代苯l‑薄荷醇类p2y12受体拮抗剂及其用途 |
CN105111118B (zh) * | 2015-08-14 | 2017-04-12 | 天津小新医药科技有限公司 | L‑薄荷醇类p2y12受体拮抗剂、制备方法及其用途 |
KR20180043819A (ko) | 2015-08-24 | 2018-04-30 | 로슈 이노베이션 센터 코펜하겐 에이/에스 | Lna-g 방법 |
CN108368507B (zh) | 2015-09-02 | 2022-03-22 | 阿尔尼拉姆医药品有限公司 | 程序性细胞死亡1配体1(PD-L1)的iRNA组合物及其使用方法 |
EP3352753A4 (fr) | 2015-09-24 | 2019-03-13 | The Regents of The University of California | Molécules de type sphingolipide synthétiques, médicaments, procédés pour leur synthèse et procédés de traitement |
US20180273577A1 (en) | 2015-09-24 | 2018-09-27 | Ionis Pharmaceuticals, Inc. | Modulators of kras expression |
WO2017053995A1 (fr) * | 2015-09-25 | 2017-03-30 | Ionis Pharmaceuticals, Inc. | Composés antisens conjugués et leur utilisation |
PT3353303T (pt) | 2015-09-25 | 2023-10-10 | Academisch Ziekenhuis Leiden | Composições e métodos para modulação da expressão de ataxina 3 |
US20180273948A1 (en) * | 2015-09-25 | 2018-09-27 | Tarveda Therapeutics, Inc. | RNAi CONJUGATES, PARTICLES AND FORMULATIONS THEREOF |
JP2018528783A (ja) | 2015-09-25 | 2018-10-04 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | コンジュゲートアンチセンス化合物及びその使用 |
JOP20210043A1 (ar) * | 2015-10-01 | 2017-06-16 | Arrowhead Pharmaceuticals Inc | تراكيب وأساليب لتثبيط تعبير جيني للـ lpa |
KR20180073584A (ko) | 2015-10-02 | 2018-07-02 | 로슈 이노베이션 센터 코펜하겐 에이/에스 | 올리고뉴클레오타이드 접합 방법 |
SG11201802870RA (en) | 2015-10-09 | 2018-05-30 | Univ Southampton | Modulation of gene expression and screening for deregulated protein expression |
EP3394258B1 (fr) | 2015-10-22 | 2021-09-22 | Roche Innovation Center Copenhagen A/S | Essai de dépistage de la toxicité in vitro |
WO2017068087A1 (fr) | 2015-10-22 | 2017-04-27 | Roche Innovation Center Copenhagen A/S | Procédé de détection d'oligonucléotides |
PE20181180A1 (es) * | 2015-11-06 | 2018-07-20 | Ionis Pharmaceuticals Inc | MODULAR LA EXPRESION DE APOLIPOPROTEINA (a) |
DK4119569T3 (da) | 2015-11-06 | 2024-08-12 | Ionis Pharmaceuticals Inc | Konjugerede antisense-forbindelser til anvendelse i behandling |
PL3377510T3 (pl) * | 2015-11-16 | 2021-05-04 | F. Hoffmann-La Roche Ag | Amidofosforyn klastra GalNAc |
US11058709B1 (en) | 2015-12-04 | 2021-07-13 | Ionis Pharmaceuticals, Inc. | Methods of treating breast cancer |
US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
CA3005256A1 (fr) | 2015-12-14 | 2017-06-22 | Cold Spring Harbor Laboratory | Oligomeres antisens destines au traitement du retard mental dominant autosomique 5 et du syndrome de dravet |
EP3400300A4 (fr) | 2016-01-05 | 2019-08-07 | Ionis Pharmaceuticals, Inc. | Procédés pour réduire l'expression de lrrk2 |
JP2019503176A (ja) | 2016-01-12 | 2019-02-07 | インターロイキン ジェネティクス, インコーポレイテッド | 処置に対する応答を予測するための方法 |
US11530409B2 (en) | 2016-01-26 | 2022-12-20 | Nissan Chemical Corporation | Single-stranded oligonucleotide |
EP3409780B1 (fr) * | 2016-01-29 | 2021-01-20 | Kyowa Kirin Co., Ltd. | Complexe d'acides nucléiques |
EP3408391A4 (fr) * | 2016-01-31 | 2019-08-28 | University of Massachusetts | Oligonucléotides ramifiés |
UY37146A (es) | 2016-03-07 | 2017-09-29 | Arrowhead Pharmaceuticals Inc | Ligandos de direccionamiento para compuestos terapéuticos |
AU2017229778A1 (en) | 2016-03-09 | 2018-08-16 | Ionis Pharmaceuticals, Inc. | Methods and compositions for inhibiting PMP22 expression |
PE20230157A1 (es) | 2016-03-14 | 2023-02-01 | Hoffmann La Roche | Oligonucleotidos para reducir la expresion de pd-l1 |
WO2017161168A1 (fr) | 2016-03-16 | 2017-09-21 | Ionis Pharmaceuticals, Inc. | Modulation d'expression de dyrk1b |
EP3429690A4 (fr) | 2016-03-16 | 2019-10-23 | Ionis Pharmaceuticals, Inc. | Procédés pour moduler keap1 |
EP3228326A1 (fr) * | 2016-04-05 | 2017-10-11 | Silence Therapeutics GmbH | Acide nucléique lié à un glycoconjugué trivalent |
MA45478A (fr) * | 2016-04-11 | 2019-02-20 | Arbutus Biopharma Corp | Compositions de conjugués d'acides nucléiques ciblés |
WO2017180835A1 (fr) | 2016-04-13 | 2017-10-19 | Ionis Pharmaceuticals, Inc. | Procédés de réduction de l'expression de c9orf72 |
US11248019B2 (en) | 2016-04-14 | 2022-02-15 | Hoffmann-La Roche Inc. | Trityl-mono-GalNAc compounds and their use |
MA45295A (fr) | 2016-04-19 | 2019-02-27 | Alnylam Pharmaceuticals Inc | Composition d'arni de protéine de liaison de lipoprotéines haute densité (hdlbp/vigiline) et procédés pour les utiliser |
US11390867B2 (en) | 2016-04-29 | 2022-07-19 | Nanyang Technological University | G-quadruplex-containing antisense oligonucleotides |
MA45270A (fr) | 2016-05-04 | 2017-11-09 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
KR102608220B1 (ko) | 2016-05-06 | 2023-11-29 | 아이오니스 파마수티컬즈, 인코포레이티드 | Glp-1 수용체 리간드 모이어티 컨쥬게이트된 올리고뉴클레오티드 및 이의 용도 |
US11479818B2 (en) | 2016-06-17 | 2022-10-25 | Hoffmann-La Roche Inc. | In vitro nephrotoxicity screening assay |
MA45496A (fr) | 2016-06-17 | 2019-04-24 | Hoffmann La Roche | Molécules d'acide nucléique pour la réduction de l'arnm de padd5 ou pad7 pour le traitement d'une infection par l'hépatite b |
JP7049271B2 (ja) | 2016-06-17 | 2022-04-06 | エフ.ホフマン-ラ ロシュ アーゲー | インビトロ腎毒性スクリーニングアッセイ |
CA3023514A1 (fr) | 2016-06-17 | 2017-12-21 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression de gys1 |
KR102418185B1 (ko) | 2016-06-22 | 2022-07-06 | 프로큐알 테라퓨틱스 Ⅱ 비.브이. | 단일 가닥 rna-편집 올리고뉴클레오타이드 |
KR102520362B1 (ko) | 2016-06-30 | 2023-04-10 | 쿄와 기린 가부시키가이샤 | 당쇄 리간드가 링커를 통해 올리고뉴클레오티드와 결합한 핵산 복합체 |
EP3481430A4 (fr) | 2016-07-11 | 2020-04-01 | Translate Bio Ma, Inc. | Conjugués de type acide nucléique et leurs utilisations |
IL291323B2 (en) | 2016-07-15 | 2023-09-01 | Am Chemicals Llc | Solid non-nucleoside supports and phosphoramidite building blocks for oligonucleotide synthesis |
FI3484524T3 (fi) | 2016-07-15 | 2023-01-13 | YHDISTEITÄ JA MENETELMIÄ SMN2:n MODULOIMISEKSI | |
CA3033368A1 (fr) | 2016-08-12 | 2018-02-15 | University Of Massachusetts | Oligonucleotides conjugues |
EP3500581A4 (fr) | 2016-08-17 | 2021-10-06 | Solstice Biologics, Ltd. | Constructions polynucléotidiques |
SG10201912835QA (en) | 2016-09-02 | 2020-02-27 | Arrowhead Pharmaceuticals Inc | Targeting ligands |
JOP20190065A1 (ar) | 2016-09-29 | 2019-03-28 | Ionis Pharmaceuticals Inc | مركبات وطرق لتقليل التعبير عن tau |
US11400161B2 (en) | 2016-10-06 | 2022-08-02 | Ionis Pharmaceuticals, Inc. | Method of conjugating oligomeric compounds |
EP3532044A4 (fr) | 2016-10-27 | 2020-07-29 | California Institute of Technology | Compositions d'inhibiteur de hdac pour la réactivation du chromosome x |
JOP20190104A1 (ar) | 2016-11-10 | 2019-05-07 | Ionis Pharmaceuticals Inc | مركبات وطرق لتقليل التعبير عن atxn3 |
EP3538654A1 (fr) * | 2016-11-11 | 2019-09-18 | Janssen BioPharma, Inc. | Stratégie de ciblage d'oligonucléotide pour l'adnccc du vhb |
TW202313978A (zh) | 2016-11-23 | 2023-04-01 | 美商阿尼拉製藥公司 | 絲胺酸蛋白酶抑制因子A1 iRNA組成物及其使用方法 |
EP4035659A1 (fr) | 2016-11-29 | 2022-08-03 | PureTech LYT, Inc. | Exosomes destinés à l'administration d'agents thérapeutiques |
WO2018102745A1 (fr) | 2016-12-02 | 2018-06-07 | Cold Spring Harbor Laboratory | Modulation de l'expression de lnc05 |
CA3047076A1 (fr) * | 2016-12-13 | 2018-06-21 | Am Sciences Inc | Composition pharmaceutique pour la prevention ou le traitement de l'hepatite b |
TW202317151A (zh) | 2016-12-16 | 2023-05-01 | 美商阿尼拉製藥公司 | 使用甲狀腺素運載蛋白(TTR)iRNA組成物於治療或預防TTR相關疾病之方法 |
CN108239644B (zh) * | 2016-12-23 | 2021-05-28 | 苏州瑞博生物技术股份有限公司 | 一种小干扰核酸和药物组合物及其用途 |
US10329620B2 (en) | 2017-01-12 | 2019-06-25 | Cardioforecast Ltd. | Methods and kits for treating cardiovascular disease |
WO2018130583A1 (fr) | 2017-01-13 | 2018-07-19 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens pour moduler l'expression de nfkb1 |
EP3568481A1 (fr) | 2017-01-13 | 2019-11-20 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens pour moduler l'expression de relb |
WO2018130582A1 (fr) | 2017-01-13 | 2018-07-19 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens pour moduler l'expression de rel |
US20190345495A1 (en) | 2017-01-13 | 2019-11-14 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating nfkb2 expression |
US20200216845A1 (en) | 2017-01-13 | 2020-07-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating rela expression |
AU2018215440A1 (en) | 2017-02-06 | 2019-08-29 | Nissan Chemical Corporation | Single-stranded oligonucleotide |
WO2018165564A1 (fr) * | 2017-03-09 | 2018-09-13 | Ionis Pharmaceuticals, Inc. | Composés oligomères modifiés par morpholino |
KR102520654B1 (ko) | 2017-03-10 | 2023-04-10 | 고쿠리츠켄큐카이하츠호진 고쿠리츠 세이쿠이료켄큐센타 | 안티센스 올리고뉴클레오티드 및 당원병 Ia형 예방 또는 치료용 조성물 |
JOP20190215A1 (ar) | 2017-03-24 | 2019-09-19 | Ionis Pharmaceuticals Inc | مُعدّلات التعبير الوراثي عن pcsk9 |
RS63836B1 (sr) | 2017-04-05 | 2023-01-31 | Silence Therapeutics Gmbh | Proizvodi i sastavi |
EP3385272A1 (fr) * | 2017-04-05 | 2018-10-10 | Silence Therapeutics GmbH | Nouveaux conjugués de ligand d'oligonucléotide |
WO2018191278A2 (fr) | 2017-04-11 | 2018-10-18 | Arbutus Biopharma Corporation | Compositions ciblées |
AU2018254437A1 (en) | 2017-04-18 | 2019-11-28 | Alnylam Pharmaceuticals, Inc. | Methods for the treatment of subjects having a hepatitis B virus (HBV) infection |
WO2018215049A1 (fr) | 2017-05-23 | 2018-11-29 | F. Hoffmann-La Roche Ag | Procédé de préparation de conjugués d'oligonucléotides galnac |
JP6952366B2 (ja) * | 2017-05-26 | 2021-10-20 | 国立研究開発法人国立循環器病研究センター | Pcsk9を標的としたアンチセンス核酸 |
CN111050806A (zh) | 2017-06-02 | 2020-04-21 | 波涛生命科学有限公司 | 寡核苷酸组合物及其使用方法 |
WO2018223073A1 (fr) * | 2017-06-02 | 2018-12-06 | Wave Life Sciences Ltd. | Compositions d'oligonucléotides et leurs procédés d'utilisation |
WO2018226788A1 (fr) * | 2017-06-07 | 2018-12-13 | University Of Massachusetts | Oligonucléotides anti-adam33 et procédés associés |
US10844377B2 (en) | 2017-06-23 | 2020-11-24 | University Of Massachusetts | Two-tailed self-delivering siRNA |
WO2019014530A1 (fr) | 2017-07-13 | 2019-01-17 | Alnylam Pharmaceuticals Inc. | Compositions d'arni de lactate déshydrogénase a (ldha) et leurs procédés d'utilisation |
JP7384033B2 (ja) | 2017-07-26 | 2023-11-21 | 日産化学株式会社 | 一本鎖オリゴヌクレオチド |
TW201920668A (zh) * | 2017-08-02 | 2019-06-01 | 日商協和醱酵麒麟有限公司 | 核酸複合體 |
WO2019027015A1 (fr) * | 2017-08-02 | 2019-02-07 | 協和発酵キリン株式会社 | Complexe d'acide nucléique |
WO2019030313A2 (fr) | 2017-08-11 | 2019-02-14 | Roche Innovation Center Copenhagen A/S | Oligonucléotides pour la modulation de l'expression de ube3c |
CA3073213A1 (fr) | 2017-08-17 | 2019-02-21 | Alnylam Pharmaceuticals, Inc. | Composes reversir tm reglables |
US11197884B2 (en) | 2017-08-18 | 2021-12-14 | Ionis Pharmaceuticals, Inc. | Modulation of the notch signaling pathway for treatment of respiratory disorders |
WO2019038228A1 (fr) | 2017-08-22 | 2019-02-28 | Roche Innovation Center Copenhagen A/S | Oligonucléotides pour la modulation de l'expression de tom1 |
SG10202108375XA (en) | 2017-08-25 | 2021-09-29 | Stoke Therapeutics Inc | Antisense oligomers for treatment of conditions and diseases |
WO2019051173A1 (fr) | 2017-09-08 | 2019-03-14 | Ionis Pharmaceuticals, Inc. | Modulateurs de l'expression de smad7 |
KR20200100601A (ko) * | 2017-09-14 | 2020-08-26 | 얀센 바이오파마, 인크. | GalNAc 유도체 |
AU2018338787A1 (en) | 2017-09-29 | 2020-04-16 | Intellia Therapeutics, Inc. | Compositions and methods for TTR gene editing and treating ATTR amyloidosis |
EP3585162B1 (fr) | 2017-09-29 | 2023-08-30 | Regeneron Pharmaceuticals, Inc. | Rongeurs comprenant un locus ttr humanisé et procédés d'utilisation |
EP3694995A1 (fr) | 2017-10-13 | 2020-08-19 | Roche Innovation Center Copenhagen A/S | Procédés d'identification de variants d'oligonucléotides phosphorothioate stéréodéfinis améliorés d'oligonucléotides antisens mettant en uvre des sous-bibliothèques d'oligonucléotides partiellement stéréodéfinis |
MA52151A (fr) | 2017-10-16 | 2020-05-06 | Hoffmann La Roche | Molécule d'acide nucléique pour la réduction de l'arnm de papd5 et de papd7 pour le traitement d'une infection par l'hépatite b |
US11866701B2 (en) | 2017-11-01 | 2024-01-09 | Alnylam Pharmaceuticals, Inc. | Complement component C3 iRNA compositions and methods of use thereof |
TWI809004B (zh) | 2017-11-09 | 2023-07-21 | 美商Ionis製藥公司 | 用於降低snca表現之化合物及方法 |
WO2019099610A1 (fr) | 2017-11-16 | 2019-05-23 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de kisspeptine 1 (kiss1) et leurs méthodes d'utilisation |
EP3714054A1 (fr) | 2017-11-20 | 2020-09-30 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de composant p amyloïde serique et leurs procédés d'utilisation |
CA3083968C (fr) | 2017-12-01 | 2024-04-23 | Suzhou Ribo Life Science Co., Ltd. | Oligonucleotide double brin, composition et conjugue comprenant un oligonucleotide double brin, procede de preparation et utilisation associes |
CN118236391A (zh) * | 2017-12-01 | 2024-06-25 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
US11414665B2 (en) | 2017-12-01 | 2022-08-16 | Suzhou Ribo Life Science Co., Ltd. | Nucleic acid, composition and conjugate comprising the same, and preparation method and use thereof |
CN111050807B (zh) * | 2017-12-01 | 2024-05-28 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
CN110997917B (zh) * | 2017-12-01 | 2024-04-09 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
CN110945130B (zh) * | 2017-12-01 | 2024-04-09 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
CN110945131B (zh) * | 2017-12-01 | 2024-05-28 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
CN111344408A (zh) | 2017-12-11 | 2020-06-26 | 哥本哈根罗氏创新中心 | 用于调控fndc3b表达的寡核苷酸 |
WO2019115417A2 (fr) | 2017-12-12 | 2019-06-20 | Roche Innovation Center Copenhagen A/S | Oligonucléotides pour la modulation de l'expression de rb1 |
JP2021506239A (ja) | 2017-12-14 | 2021-02-22 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | 複合アンチセンス化合物及びその使用 |
CN111727252A (zh) | 2017-12-18 | 2020-09-29 | 阿尔尼拉姆医药品有限公司 | 高速泳动族盒-1(HMGB1)iRNA组合物及其使用方法 |
WO2019126641A2 (fr) | 2017-12-21 | 2019-06-27 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression de la frataxine |
CN111512160B (zh) | 2017-12-21 | 2024-04-09 | 豪夫迈·罗氏有限公司 | Htra1 rna拮抗剂的伴随诊断 |
EP4092117A1 (fr) | 2017-12-22 | 2022-11-23 | Roche Innovation Center Copenhagen A/S | Oligonucléotides gapmer comprenant une liaison internucléoside phosphorodithioate |
US11597926B2 (en) | 2017-12-22 | 2023-03-07 | Roche Innovation Center Copenhagen A/S | Thiophosphoramidites |
EP4074724A1 (fr) | 2017-12-22 | 2022-10-19 | Roche Innovation Center Copenhagen A/S | Oligonucléotides comprenant une liaison internucléoside phosphorodithioate |
CN109957566B (zh) * | 2017-12-26 | 2023-08-25 | 广州市锐博生物科技有限公司 | 修饰的寡核苷酸和可用于合成修饰的寡核苷酸的化合物 |
WO2019127004A1 (fr) | 2017-12-26 | 2019-07-04 | 广州市锐博生物科技有限公司 | Oligonucléotides modifiés et composé qui peut être utilisé pour la synthèse de ceux-ci |
CN110959011B (zh) | 2017-12-29 | 2023-03-28 | 苏州瑞博生物技术股份有限公司 | 缀合物及其制备方法和用途 |
EP3737758A1 (fr) | 2018-01-10 | 2020-11-18 | Roche Innovation Center Copenhagen A/S | Oligonucléotides pour moduler l'expression de pias4 |
WO2019140102A1 (fr) * | 2018-01-10 | 2019-07-18 | Translate Bio Ma, Inc. | Compositions et méthodes pour faciliter l'administration d'acides nucléiques synthétiques dans des cellules |
SG11202006528XA (en) | 2018-01-12 | 2020-08-28 | Bristol Myers Squibb Co | Antisense oligonucleotides targeting alpha-synuclein and uses thereof |
US20210095275A1 (en) | 2018-01-12 | 2021-04-01 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating gsk3b expression |
JP7455746B2 (ja) | 2018-01-12 | 2024-03-26 | ブリストル-マイヤーズ スクイブ カンパニー | アルファ-シヌクレインを標的とするアンチセンスオリゴヌクレオチドおよびその使用 |
PE20210172A1 (es) | 2018-01-12 | 2021-01-29 | Roche Innovation Ct Copenhagen As | Oligonucleotidos antisentido para alfa-sinucleina y usos de los mismos |
MX2020007369A (es) | 2018-01-15 | 2020-10-28 | Ionis Pharmaceuticals Inc | Moduladores de la expresion de dnm2. |
US20210095276A1 (en) | 2018-01-17 | 2021-04-01 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating erc1 expression |
WO2019141723A1 (fr) | 2018-01-18 | 2019-07-25 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens ciblant srebp1 |
WO2019145386A1 (fr) | 2018-01-26 | 2019-08-01 | Roche Innovation Center Copenhagen A/S | Oligonucléotides pour la modulation de l'expression de csnk1d |
WO2019157531A1 (fr) | 2018-02-12 | 2019-08-15 | Ionis Pharmaceuticals, Inc. | Composés modifiés et leurs utilisations |
CN112041439A (zh) | 2018-02-14 | 2020-12-04 | 深度基因组学公司 | 用于威尔森病的寡核苷酸疗法 |
SG11202007652UA (en) | 2018-02-21 | 2020-09-29 | Bristol Myers Squibb Co | Camk2d antisense oligonucleotides and uses thereof |
TWI840345B (zh) | 2018-03-02 | 2024-05-01 | 美商Ionis製藥公司 | Irf4表現之調節劑 |
US11732260B2 (en) | 2018-03-02 | 2023-08-22 | Ionis Pharmaceuticals, Inc. | Compounds and methods for the modulation of amyloid-β precursor protein |
KR20210130854A (ko) * | 2018-03-09 | 2021-11-01 | 다이이찌 산쿄 가부시키가이샤 | 당원병 Ia형 치료약 |
US11661601B2 (en) | 2018-03-22 | 2023-05-30 | Ionis Pharmaceuticals, Inc. | Methods for modulating FMR1 expression |
CN112055749A (zh) | 2018-04-05 | 2020-12-08 | 豪夫迈·罗氏有限公司 | Fubp1抑制剂用于治疗乙型肝炎病毒感染的用途 |
CN112041440A (zh) | 2018-04-11 | 2020-12-04 | Ionis制药公司 | Ezh2表达的调节剂 |
BR112020022512A2 (pt) | 2018-05-04 | 2021-05-04 | Stoke Therapeutics, Inc. | métodos e composições para tratamento de doença de armazenamento de éster de colesteril |
CN112105745A (zh) | 2018-05-07 | 2020-12-18 | 罗氏创新中心哥本哈根有限公司 | 用于寡核苷酸治疗剂的大规模平行发现方法 |
EP3790972A1 (fr) | 2018-05-08 | 2021-03-17 | Regulus Therapeutics Inc. | Oligonucléotide modifié conjugué à galnac en tant qu'inhibiteur de mir-122 ayant une activité antivirale contre le vhc à effet secondaire d'hyperbilirubinémie réduit |
SG11202010215TA (en) | 2018-05-09 | 2020-11-27 | Ionis Pharmaceuticals Inc | Compounds and methods for reducing atxn3 expression |
CN112041446B (zh) * | 2018-05-09 | 2022-08-30 | Ionis制药公司 | 用于减少fxi表达的化合物和方法 |
JP7346460B2 (ja) | 2018-05-14 | 2023-09-19 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | アンジオテンシノーゲン(AGT)iRNA組成物及びその使用方法 |
AU2019287635A1 (en) | 2018-06-14 | 2020-12-17 | Ionis Pharmaceuticals, Inc. | Compounds and methods for increasing STMN2 expression |
TWI833770B (zh) | 2018-06-27 | 2024-03-01 | 美商Ionis製藥公司 | 用於減少 lrrk2 表現之化合物及方法 |
CR20210178A (es) | 2018-07-03 | 2021-05-11 | Hoffmann La Roche | OLIGONUCLEÓTIDOS PARA MODULAR LA EXPRESIÓN DE TAU (Divisional 2021-0058) |
WO2020007826A1 (fr) | 2018-07-05 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens ciblant mbtps1 |
WO2020011744A2 (fr) | 2018-07-11 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens ciblant cers5 |
WO2020011745A2 (fr) | 2018-07-11 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Oligonucléotides antisens ciblant cers6 |
KR20210033004A (ko) | 2018-07-13 | 2021-03-25 | 에프. 호프만-라 로슈 아게 | Rtel1의 발현을 조절하기 위한 올리고뉴클레오티드 |
MX2021000922A (es) | 2018-07-25 | 2021-03-31 | Ionis Pharmaceuticals Inc | Compuestos y metodos para reducir la expresion de la atxn2. |
WO2020025563A1 (fr) | 2018-07-31 | 2020-02-06 | Roche Innovation Center Copenhagen A/S | Oligonucléotides comprenant une liaison internucléosidique phosphorotrithioate |
WO2020025527A1 (fr) | 2018-07-31 | 2020-02-06 | Roche Innovation Center Copenhagen A/S | Oligonucléotides comprenant une liaison internucléosidique phosphorotrithioate |
EP3833397A4 (fr) | 2018-08-08 | 2023-06-14 | Arcturus Therapeutics, Inc. | Compositions et agents contre la stéatohépatite non alcoolique |
EP3833763A4 (fr) | 2018-08-10 | 2023-07-19 | University of Massachusetts | Oligonucléotides modifiés ciblant des snp |
AR114551A1 (es) | 2018-08-13 | 2020-09-16 | Alnylam Pharmaceuticals Inc | COMPOSICIONES DE AGENTES DE ARNhd CONTRA EL VIRUS DE HEPATITIS B (HBV) Y MÉTODOS PARA SU USO |
EP3842534A4 (fr) | 2018-08-21 | 2022-07-06 | Suzhou Ribo Life Science Co., Ltd. | Acide nucléique, composition et conjugué contenant un acide nucléique et leur procédé d'utilisation |
US20220160870A1 (en) | 2018-08-28 | 2022-05-26 | Roche Innovation Center Copenhagen A/S | Neoantigen engineering using splice modulating compounds |
AU2019344776A1 (en) | 2018-09-18 | 2021-01-21 | Alnylam Pharmaceuticals, Inc. | Ketohexokinase (KHK) iRNA compositions and methods of use thereof |
TW202423454A (zh) | 2018-09-19 | 2024-06-16 | 美商Ionis製藥公司 | Pnpla3表現之調節劑 |
JP7376952B2 (ja) | 2018-09-30 | 2023-11-09 | スーチョウ リボ ライフ サイエンス カンパニー、リミテッド | siRNA複合体及びその調製方法と使用 |
EP3867382A4 (fr) * | 2018-10-18 | 2022-09-07 | Murdoch University | Thérapie antisens pour des états liés à ptp1b |
US10913951B2 (en) | 2018-10-31 | 2021-02-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Silencing of HNF4A-P2 isoforms with siRNA to improve hepatocyte function in liver failure |
AU2019377275A1 (en) | 2018-11-09 | 2021-03-25 | Novartis Ag | Method for reducing the risk of a cardiovascular event with conjugated antisense compounds targeting apo(a) |
TW202028222A (zh) | 2018-11-14 | 2020-08-01 | 美商Ionis製藥公司 | Foxp3表現之調節劑 |
PE20211869A1 (es) | 2018-11-15 | 2021-09-21 | Ionis Pharmaceuticals Inc | Moduladores de la expresion de irf5 |
MX2021005886A (es) | 2018-11-21 | 2021-06-23 | Ionis Pharmaceuticals Inc | Compuestos y metodos para reducir la expresion de priones. |
WO2020104649A2 (fr) | 2018-11-23 | 2020-05-28 | Sanofi | Nouvelles compositions d'arn et méthodes d'inhibition d'angptl8 |
AU2019390097A1 (en) | 2018-11-30 | 2021-07-15 | Kyowa Kirin Co., Ltd. | Nucleic acid conjugate |
JP2022515744A (ja) | 2018-12-20 | 2022-02-22 | プラクシス プレシジョン メディシンズ, インコーポレイテッド | Kcnt1関連障害の治療のための組成物及び方法 |
GB201821269D0 (en) | 2018-12-28 | 2019-02-13 | Nippon Shinyaku Co Ltd | Myostatin signal inhibitor |
KR20210110839A (ko) * | 2018-12-28 | 2021-09-09 | 쑤저우 리보 라이프 사이언스 컴퍼니, 리미티드 | 핵산, 핵산을 함유하는 조성물 및 접합체, 이의 제조 방법 및 용도 |
CN111377985B (zh) * | 2018-12-29 | 2023-11-10 | 苏州瑞博生物技术股份有限公司 | 化合物和缀合物及其制备方法和用途 |
CN113330117B (zh) * | 2019-01-18 | 2024-05-28 | 苏州瑞博生物技术股份有限公司 | 一种核酸、含有该核酸的组合物与缀合物及制备方法和用途 |
WO2020160453A1 (fr) | 2019-01-31 | 2020-08-06 | Ionis Pharmaceuticals, Inc. | Modulateurs de l'expression de yap1 |
KR20210132681A (ko) | 2019-02-20 | 2021-11-04 | 로슈 이노베이션 센터 코펜하겐 에이/에스 | 신규 포스포라미디트 |
MX2021009950A (es) | 2019-02-20 | 2021-09-21 | Roche Innovation Ct Copenhagen As | Oligonucleotidos gapmeros de fosfonoacetato. |
CN109799330B (zh) * | 2019-02-22 | 2021-03-02 | 华中科技大学同济医学院附属同济医院 | 神经氨酸及神经氨酸酶抑制剂在慢性心力衰竭中的应用 |
EP3931348B1 (fr) | 2019-02-26 | 2023-08-09 | Roche Innovation Center Copenhagen A/S | Procédé de formulation d'oligonucléotides |
AU2020227824A1 (en) | 2019-02-27 | 2021-08-26 | Ionis Pharmaceuticals, Inc. | Modulators of MALAT1 expression |
WO2020172755A1 (fr) * | 2019-02-28 | 2020-09-03 | Deep Genomics Incorporated | Agrégats à ligands et procédés d'utilisation et de préparation |
AU2020253821A1 (en) | 2019-03-29 | 2021-10-28 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating UBE3A-ATS |
US20220177894A1 (en) | 2019-04-02 | 2022-06-09 | Proqr Therapeutics Ii B.V. | Antisense oligonucleotides for immunotherapy |
CN113906139A (zh) | 2019-04-03 | 2022-01-07 | 百时美施贵宝公司 | Angptl2反义寡核苷酸及其用途 |
CN113811613B (zh) | 2019-05-22 | 2024-04-05 | 苏州瑞博生物技术股份有限公司 | 核酸、药物组合物与缀合物及制备方法和用途 |
JP2022533419A (ja) | 2019-05-22 | 2022-07-22 | スーチョウ リボ ライフ サイエンス カンパニー、リミテッド | 核酸、薬物組成物及び複合体ならびに調製方法と使用 |
WO2020233655A1 (fr) | 2019-05-22 | 2020-11-26 | 苏州瑞博生物技术股份有限公司 | Acide nucléique, composition pharmaceutique, conjugué, procédé de préparation et utilisation |
AU2020280438A1 (en) * | 2019-05-22 | 2021-12-16 | Suzhou Ribo Life Science Co., Ltd. | Nucleic acid, pharmaceutical composition, conjugate, preparation method, and use |
EP3992290A4 (fr) | 2019-05-24 | 2023-11-15 | Suzhou Ribo Life Science Co., Ltd. | Acide nucléique, composition pharmaceutique et conjugué contenant un acide nucléique et leur procédé d'utilisation |
JP2022535708A (ja) | 2019-05-24 | 2022-08-10 | スーチョウ リボ ライフ サイエンス カンパニー、リミテッド | 核酸、薬物組成物及び複合体ならびに調製方法と使用 |
JP2022534702A (ja) | 2019-05-24 | 2022-08-03 | スーチョウ リボ ライフ サイエンス カンパニー、リミテッド | 核酸、薬物組成物及び複合体ならびに調製方法と使用 |
US20220243203A1 (en) | 2019-05-28 | 2022-08-04 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing fus expression |
TW202113079A (zh) | 2019-05-31 | 2021-04-01 | 美商艾利格斯醫療公司 | 經修飾之間隙子寡核苷酸及其使用方法 |
WO2020247452A1 (fr) | 2019-06-04 | 2020-12-10 | Regeneron Pharmaceuticals, Inc. | Animaux non humains comprenant un locus ttr humanisé ayant une mutation bêta-slip et procédés d'utilisation |
CA3143047A1 (fr) | 2019-06-25 | 2020-12-30 | Amgen Inc. | Procedes de purification d'oligonucleotides lies a des glucides |
EP3956450A4 (fr) | 2019-07-26 | 2022-11-16 | Ionis Pharmaceuticals, Inc. | Composés et procédés pour la modulation de gfap |
EP4007812A1 (fr) | 2019-08-01 | 2022-06-08 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de la famille des serpines 2 (serpinf2) et leurs procedes d'utilisation |
WO2021022108A2 (fr) | 2019-08-01 | 2021-02-04 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de carboxypeptidase b2 (cpb2) et leurs procédés d'utilisation |
BR112022002307A2 (pt) | 2019-08-09 | 2022-06-28 | Univ Massachusetts | Oligonucleotídeos quimicamente modificados que têm como alvo snps |
EP4013870A1 (fr) | 2019-08-13 | 2022-06-22 | Alnylam Pharmaceuticals, Inc. | Compositions d'agent d'arni à sous-unité de protéine ribosomale 25 (rps25) et leurs procédés d'utilisation |
EP4013767A4 (fr) * | 2019-08-15 | 2023-10-25 | Ionis Pharmaceuticals, Inc. | Composés oligomères modifiés par liaison et leurs utilisations |
CN115176011A (zh) | 2019-08-27 | 2022-10-11 | 赛诺菲 | 用于抑制pcsk9的组合物和方法 |
TW202122093A (zh) | 2019-08-29 | 2021-06-16 | 大陸商蘇州瑞博生物技術股份有限公司 | 化合物、藥物綴合物、試劑盒及其用途 |
EP4022062A1 (fr) | 2019-08-30 | 2022-07-06 | Alnylam Pharmaceuticals, Inc. | Chaîne légère neurofilamentaire (nfl) en tant que biomarqueur pour la polyneuropathie liée une amylose à transthyrétine |
WO2021046260A1 (fr) | 2019-09-03 | 2021-03-11 | Arcturus Therapeutics, Inc. | Administration de conjugués thérapeutiquement actifs médiée par un récepteur d'asialoglycoprotéine |
WO2021049504A1 (fr) * | 2019-09-10 | 2021-03-18 | 第一三共株式会社 | Conjugué galnac-oligonucléotide pour une utilisation d'administration ciblée sur le foie, et son procédé de production |
CN114423430A (zh) | 2019-09-20 | 2022-04-29 | 豪夫迈·罗氏有限公司 | 使用核心蛋白别构调节剂治疗hbv感染的方法 |
WO2021074772A1 (fr) | 2019-10-14 | 2021-04-22 | Astrazeneca Ab | Modulateurs de l'expression de pnpla3 |
EP4045652A1 (fr) | 2019-10-18 | 2022-08-24 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de membre de la famille des transporteurs de solutés et leurs procédés d'utilisation |
BR112022007540A2 (pt) | 2019-10-22 | 2022-07-12 | Alnylam Pharmaceuticals Inc | Composições de irna de componente complementar c3 e métodos de uso das mesmas |
TW202132567A (zh) | 2019-11-01 | 2021-09-01 | 美商阿尼拉製藥公司 | 亨汀頓蛋白(HTT)iRNA劑組成物及其使用方法 |
TW202132568A (zh) | 2019-11-13 | 2021-09-01 | 美商阿尼拉製藥公司 | 用於治療血管收縮素原相關病症之方法及組成物 |
WO2021102373A1 (fr) | 2019-11-22 | 2021-05-27 | Alnylam Pharmaceuticals, Inc. | Compositions d'agent arni d'ataxine 3 (atxn3) et leurs procédés d'utilisation |
CN112876534B (zh) * | 2019-11-29 | 2024-02-09 | 苏州瑞博生物技术股份有限公司 | 肝靶向化合物及缀合物 |
MX2022006433A (es) | 2019-12-13 | 2022-06-23 | Alnylam Pharmaceuticals Inc | Composiciones de agentes de acido ribonucleico de interferencia (arni) del marco de lectura abierto 72 del cromosoma 9 humano (c9orf72) y metodos de uso de los mismos. |
TW202138559A (zh) | 2019-12-16 | 2021-10-16 | 美商阿尼拉製藥公司 | 含類PATATIN磷脂酶結構域3(PNPLA3)iRNA組成物及其使用方法 |
JP2023506546A (ja) | 2019-12-19 | 2023-02-16 | エフ. ホフマン-ラ ロシュ エージー. | B型肝炎ウイルス感染症を処置するためのsept9阻害剤の使用 |
WO2021122993A1 (fr) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Utilisation d'inhibiteurs de saraf pour traiter une infection par le virus de l'hépatite b |
WO2021122921A1 (fr) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Utilisation d'inhibiteurs de cops3 pour traiter une infection par le virus de l'hépatite b |
JP2023506550A (ja) | 2019-12-19 | 2023-02-16 | エフ. ホフマン-ラ ロシュ エージー. | B型肝炎ウイルス感染症を処置するためのsbds阻害剤の使用 |
WO2021122869A1 (fr) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Utilisation d'inhibiteurs de scamp3 pour traiter une infection par le virus de l'hépatite b |
AU2020415322A1 (en) | 2019-12-24 | 2022-06-16 | F. Hoffmann-La Roche Ag | Pharmaceutical combination of antiviral agents targeting HBV and/or an immune modulator for treatment of HBV |
WO2021130266A1 (fr) | 2019-12-24 | 2021-07-01 | F. Hoffmann-La Roche Ag | Association pharmaceutique d'un oligonucléotide thérapeutique ciblant le vhb et un agoniste de tlr7 pour le traitement du vhb |
KR20220119616A (ko) | 2019-12-24 | 2022-08-30 | 에프. 호프만-라 로슈 아게 | Tlr7 효현제를 이용하여 바이러스 감염을 치료하는 방법 |
WO2021153687A1 (fr) | 2020-01-30 | 2021-08-05 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Complexe d'acide nucléique et composition pharmaceutique le contenant |
US20230136787A1 (en) | 2020-02-10 | 2023-05-04 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing vegf-a expression |
KR20220143106A (ko) | 2020-02-18 | 2022-10-24 | 알닐람 파마슈티칼스 인코포레이티드 | 아포지질단백질 C3 (APOC3) iRNA 조성물 및 이의 사용 방법 |
JOP20220201A1 (ar) | 2020-02-28 | 2023-01-30 | Ionis Pharmaceuticals Inc | مركبات وطرق لتعديل smn2 |
EP4114947A1 (fr) | 2020-03-05 | 2023-01-11 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de composant c3 du complément et leurs procédés d'utilisation pour le traitement ou la prévention de maladies associées au composant c3 du complément |
WO2021178736A1 (fr) | 2020-03-06 | 2021-09-10 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de cétohexokinase (khk) et leurs procédés d'utilisation |
IL296106A (en) | 2020-03-06 | 2022-11-01 | Alnylam Pharmaceuticals Inc | Compositions and methods for inhibiting expression of transthyretin (ttr) |
WO2021188611A1 (fr) | 2020-03-18 | 2021-09-23 | Alnylam Pharmaceuticals, Inc. | Compositions et méthodes pour traiter des sujets ayant un variant de gène d'alanine-glyoxylate aminotransférase hétérozygote (agxt) |
AU2021244329A1 (en) | 2020-03-23 | 2022-09-29 | Amgen Inc. | Monoclonal antibodies to chemically-modified nucleic acids and uses thereof |
CN116209759A (zh) | 2020-03-26 | 2023-06-02 | 阿尔尼拉姆医药品有限公司 | 冠状病毒iRNA组合物及其使用方法 |
WO2021193965A1 (fr) * | 2020-03-26 | 2021-09-30 | 国立研究開発法人国立循環器病研究センター | Acide nucléique antisens ciblant l'apoc3 |
MX2022012493A (es) | 2020-04-06 | 2022-10-27 | Alnylam Pharmaceuticals Inc | Composiciones y metodos para el silenciamiento de la expresion de miocilina (myoc). |
WO2021206917A1 (fr) | 2020-04-07 | 2021-10-14 | Alnylam Pharmaceuticals, Inc. | Compositions arni d'enzyme de conversion de l'angiotensine 2 (eca2) et procédés d'utilisation associés |
US20230159933A1 (en) | 2020-04-07 | 2023-05-25 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing scn9a expression |
WO2021206922A1 (fr) | 2020-04-07 | 2021-10-14 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de la serine protease 2 transmembranaire (tmprss2) et leurs procédés d'utilisation |
CN111575279A (zh) * | 2020-04-27 | 2020-08-25 | 江苏为真生物医药技术股份有限公司 | 利用asgpr小分子配体特异性捕获肝细胞外囊泡或循环肿瘤细胞的方法 |
EP4143319A1 (fr) | 2020-04-27 | 2023-03-08 | Alnylam Pharmaceuticals, Inc. | Compositions d'agent d'arni de l'apolipoprotéine e (apoe) et leurs procédés d'utilisation |
KR20230017789A (ko) | 2020-04-30 | 2023-02-06 | 알닐람 파마슈티칼스 인코포레이티드 | 보체 인자 B (CFB) iRNA 조성물 및 이의 사용 방법 |
AU2021264010A1 (en) | 2020-05-01 | 2022-12-08 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating ATXN1 |
CN115867657A (zh) | 2020-05-11 | 2023-03-28 | 斯托克制药公司 | 用于治疗疾患和疾病的opa1反义寡聚物 |
EP4150077A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar de la protéine 1 de type canal transmembranaire (tmc1) |
WO2021231673A1 (fr) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar de la kinase 2 à répétition riche en leucine (lrrk2) |
EP4150087A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar de la protéine bêta 2 de jonction lacunaire (gjb2) |
EP4150078A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar d'argininosuccinate lyase (asl) |
EP4150076A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar de la protéine 2 de liaison méthyl-cpg (mecp2) |
EP4150090A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar d'otoferline (otof) |
WO2021231675A1 (fr) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar d'argininosuccinate synthétase (ass1) |
EP4150089A1 (fr) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar de rétinoschisine 1 (rs1) |
AR122534A1 (es) | 2020-06-03 | 2022-09-21 | Triplet Therapeutics Inc | Métodos para el tratamiento de los trastornos de expansión por repetición de nucleótidos asociados con la actividad de msh3 |
EP4162050A1 (fr) | 2020-06-09 | 2023-04-12 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni et leurs procédés d'utilisation pour une administration par inhalation |
WO2021249484A1 (fr) * | 2020-06-10 | 2021-12-16 | 南京明德新药研发有限公司 | Groupe conjugué et conjugué |
AU2021292296A1 (en) | 2020-06-18 | 2023-01-19 | Alnylam Pharmaceuticals, Inc. | Xanthine dehydrogenase (XDH) iRNA compositions and methods of use thereof |
AR122731A1 (es) | 2020-06-26 | 2022-10-05 | Hoffmann La Roche | Oligonucleótidos mejorados para modular la expresión de fubp1 |
JP2023532518A (ja) | 2020-06-29 | 2023-07-28 | アイオーニス ファーマシューティカルズ, インコーポレーテッド | Plp1を調節するための化合物及び方法 |
CN116113697A (zh) | 2020-07-10 | 2023-05-12 | 国家健康与医学研究院 | 用于治疗癫痫的方法和组合物 |
IL300360A (en) * | 2020-08-13 | 2023-04-01 | Amgen Inc | RNAi constructs and methods to inhibit MARC1 expression |
WO2022038211A2 (fr) | 2020-08-21 | 2022-02-24 | F. Hoffmann-La Roche Ag | Utilisation d'inhibiteurs de a1cf pour traiter une infection par le virus de l'hépatite b |
WO2022066847A1 (fr) | 2020-09-24 | 2022-03-31 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de dipeptidyle peptidase 4 (dpp4) et leurs procédés d'utilisation |
JP2023544413A (ja) | 2020-10-05 | 2023-10-23 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | Gタンパク質共役受容体75(GPR75)iRNA組成物およびその使用方法 |
CN116887842A (zh) | 2020-10-16 | 2023-10-13 | 赛诺菲 | 用于抑制angptl3的新型rna组合物和方法 |
WO2022079221A1 (fr) | 2020-10-16 | 2022-04-21 | Sanofi | Compositions d'arn et méthodes d'inhibition de lipoprotéine (a) |
EP4232582A1 (fr) | 2020-10-23 | 2023-08-30 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de la mucine 5b (muc5b) et leurs méthodes d'utilisation |
TW202237841A (zh) | 2020-11-13 | 2022-10-01 | 美商艾拉倫製藥股份有限公司 | 凝血因子V(F5)iRNA組成物及其使用方法 |
EP4136092B1 (fr) | 2020-11-18 | 2024-07-31 | Ionis Pharmaceuticals, Inc. | Composés et procédés pour moduler l'expression de l'angiotensinogène |
AU2021382146A1 (en) | 2020-11-23 | 2022-05-27 | Alpha Anomeric Sas | Nucleic acid duplexes |
EP4259795A1 (fr) | 2020-12-08 | 2023-10-18 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni du facteur de coagulation x (f10) et leurs méthodes d'utilisation |
GB2603454A (en) | 2020-12-09 | 2022-08-10 | Ucl Business Ltd | Novel therapeutics for the treatment of neurodegenerative disorders |
JP2023554346A (ja) | 2020-12-18 | 2023-12-27 | アイオーニス ファーマシューティカルズ, インコーポレーテッド | 第xii因子を調節するための化合物及び方法 |
WO2022136466A1 (fr) | 2020-12-23 | 2022-06-30 | Argonaute RNA Limited | Traitement d'une maladie cardiovasculaire |
WO2022143531A1 (fr) | 2020-12-29 | 2022-07-07 | 苏州瑞博生物技术股份有限公司 | Acide nucléique, composition et conjugué d'arnsi contenant un acide nucléique, procédé de préparation et utilisation associés |
EP4274896A1 (fr) | 2021-01-05 | 2023-11-15 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni du composant du complément 9 (c9) et leurs méthodes d'utilisation |
AU2022215065A1 (en) * | 2021-01-30 | 2023-07-27 | E-Therapeutics Plc | Conjugated oligonucleotide compounds, methods of making and uses thereof |
CA3204340A1 (fr) * | 2021-01-30 | 2022-08-04 | Ahmad Ali MORTAZAVI | Composes oligonucleotidiques conjugues, leurs procedes de fabrication et leurs utilisations |
WO2022162161A1 (fr) * | 2021-01-30 | 2022-08-04 | E-Therapeutics Plc | Composés oligonucléotidiques conjugués, leurs procédés de fabrication et leurs utilisations |
WO2022162157A1 (fr) * | 2021-01-30 | 2022-08-04 | E-Therapeutics Plc | Composés oligonucléotidiques conjugués, leurs procédés de fabrication et leurs utilisations |
TW202246500A (zh) | 2021-02-02 | 2022-12-01 | 瑞士商赫孚孟拉羅股份公司 | 用於抑制 rtel1 表現之增強型寡核苷酸 |
KR20230146048A (ko) | 2021-02-12 | 2023-10-18 | 알닐람 파마슈티칼스 인코포레이티드 | 슈퍼옥사이드 디스뮤타제 1(sod1) irna 조성물 및 슈퍼옥사이드 디스뮤타제 1- (sod1-) 관련 신경퇴행성 질환을 치료하거나 예방하기 위한 이의 사용 방법 |
EP4294449A1 (fr) * | 2021-02-18 | 2023-12-27 | Oneglobe Holdings Limited | Compositions pour conjuguer des oligonucléotides et des glucides |
EP4298220A1 (fr) | 2021-02-25 | 2024-01-03 | Alnylam Pharmaceuticals, Inc. | Compositions à base d'arni de protéine prion (prnp) et procédés et procédés d'utilisation de celles-ci |
MX2023009704A (es) | 2021-02-26 | 2023-10-23 | Alnylam Pharmaceuticals Inc | Composiciones de arni de cetohexocinasa (khk) y métodos de uso de las mismas. |
KR20230150843A (ko) | 2021-03-04 | 2023-10-31 | 알닐람 파마슈티칼스 인코포레이티드 | 안지오포이에틴-유사 3(ANGPTL3) iRNA 조성물 및 이의 사용 방법 |
CA3212650A1 (fr) | 2021-03-08 | 2022-09-15 | Les Laboratoires Servier | Oligonucleotides antisens pour inhiber l'expression de l'alpha-synucleine |
WO2022189861A1 (fr) | 2021-03-08 | 2022-09-15 | Tollys | Conjugués d'hydrates de carbone de ligands tlr3 et leurs utilisations |
EP4305169A1 (fr) | 2021-03-12 | 2024-01-17 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de la glycogène synthase kinase 3 alpha (gsk3a) et leurs procédés d'utilisation |
IL307239A (en) | 2021-03-29 | 2023-11-01 | Alnylam Pharmaceuticals Inc | Preparations containing Huntingtin IRNA factor (HTT) and methods of using them |
WO2022212153A1 (fr) | 2021-04-01 | 2022-10-06 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de proline déshydrogénase 2 (prodh2) et procédés d'utilisation associés |
TW202300645A (zh) | 2021-04-14 | 2023-01-01 | 美商戴瑟納製藥股份有限公司 | 用於調節pnpla3表現之組合物及方法 |
CA3216106A1 (fr) | 2021-04-26 | 2022-11-03 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de protease transmembranaire, de serine 6 (tmprss6) et leurs procedes d'utilisation |
WO2022232343A1 (fr) | 2021-04-29 | 2022-11-03 | Alnylam Pharmaceuticals, Inc. | Transducteur de signal et activateur de compositions d'arni du facteur de transcription 6 (stat6) et procédés d'utilisation correspondants |
WO2022232650A1 (fr) * | 2021-04-30 | 2022-11-03 | Ionis Pharmaceuticals, Inc. | Procédés de réduction de l'expression d'agt |
JP2024522068A (ja) | 2021-05-18 | 2024-06-11 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | ナトリウム-グルコース共輸送体2(sglt2)irna組成物およびその使用方法 |
EP4341405A1 (fr) | 2021-05-20 | 2024-03-27 | Korro Bio, Inc. | Procédés et compositions pour l'édition médiée par adar |
WO2022256283A2 (fr) | 2021-06-01 | 2022-12-08 | Korro Bio, Inc. | Méthodes de restauration de la fonction protéique par adar |
TW202317762A (zh) | 2021-06-02 | 2023-05-01 | 美商艾拉倫製藥股份有限公司 | 含有類PATATIN磷脂酶結構域3(PNPLA3)的iRNA組成物及其使用方法 |
IL308743A (en) | 2021-06-04 | 2024-01-01 | Alnylam Pharmaceuticals Inc | Compositions of human chromosome 9 open reading frame 72 iRNA factor (C9ORF72) and methods of using them |
JP2024523000A (ja) | 2021-06-08 | 2024-06-25 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | シュタルガルト病及び/又は網膜結合タンパク質4(rbp4)関連障害を治療又は予防するための組成物及び方法 |
MX2023015230A (es) | 2021-06-18 | 2024-01-18 | Ionis Pharmaceuticals Inc | Compuestos y metodos para reducir la expresion de ifnar1. |
KR20240040729A (ko) | 2021-06-23 | 2024-03-28 | 유니버시티 오브 매사추세츠 | 자간전증 및 기타 혈관신생 질환의 치료를 위한 최적화된 항-flt1 올리고뉴클레오타이드 화합물 |
MX2024000208A (es) * | 2021-06-24 | 2024-01-29 | Lilly Co Eli | Restos de administracion terapeutica novedosos y usos de estos. |
TW202315646A (zh) * | 2021-06-24 | 2023-04-16 | 美商美國禮來大藥廠 | 新穎之rna治療劑及其用途 |
US20230194709A9 (en) | 2021-06-29 | 2023-06-22 | Seagate Technology Llc | Range information detection using coherent pulse sets with selected waveform characteristics |
EP4363574A1 (fr) | 2021-06-29 | 2024-05-08 | Korro Bio, Inc. | Procédés et compositions pour édition médiée par adar |
CA3225469A1 (fr) | 2021-06-30 | 2023-01-05 | Alnylam Pharmaceuticals, Inc. | Procedes et compositions pour le traitement d'un trouble associe a l'angiotensinogene (agt) |
JP2024524330A (ja) * | 2021-07-02 | 2024-07-05 | 上海拓界生物医薬科技有限公司 | 核酸リガンド及びその複合体、その調製方法と用途 |
IL310003A (en) | 2021-07-08 | 2024-03-01 | Nippon Shinyaku Co Ltd | A substance that lowers nephrotoxicity |
CN118434424A (zh) | 2021-07-08 | 2024-08-02 | 日本新药株式会社 | 析出抑制剂 |
EP4368176A1 (fr) | 2021-07-08 | 2024-05-15 | Nippon Shinyaku Co., Ltd. | Agent de réduction de néphrotoxicité |
WO2023003805A1 (fr) | 2021-07-19 | 2023-01-26 | Alnylam Pharmaceuticals, Inc. | Méthodes et compositions pour traiter des sujets ayant ou ayant un risque de développer une maladie ou un trouble d'hyperoxalurie non primaire |
WO2023003995A1 (fr) | 2021-07-23 | 2023-01-26 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de bêta-caténine (ctnnb1) et leurs méthodes d'utilisation |
WO2023009687A1 (fr) | 2021-07-29 | 2023-02-02 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni de 3-hydroxy-3-méthylglutaryle-coa réductase (hmgcr) et leurs procédés d'utilisation |
JP2024530018A (ja) | 2021-08-03 | 2024-08-14 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | トランスサイレチン(TTR)iRNA組成物およびその使用方法 |
WO2023015223A2 (fr) * | 2021-08-03 | 2023-02-09 | Verve Therapeutics, Inc. | Compositions et méthodes d'administration ciblée d'arn |
PE20241132A1 (es) | 2021-08-04 | 2024-05-24 | Alnylam Pharmaceuticals Inc | Composiciones de arni y metodos para silenciar el angiotensinogeno (agt) |
TW202334413A (zh) | 2021-08-13 | 2023-09-01 | 美商艾拉倫製藥股份有限公司 | 第十二因子(F12)iRNA組成物及其使用方法 |
WO2023041508A2 (fr) | 2021-09-14 | 2023-03-23 | Argonaute RNA Limited | Traitement d'une maladie cardiovasculaire |
EP4401742A2 (fr) | 2021-09-17 | 2024-07-24 | Alnylam Pharmaceuticals, Inc. | Compositions d'arni et procédés de silençage de composant du complément 3 (c3) |
KR20240056619A (ko) * | 2021-09-18 | 2024-04-30 | 제노바 테라퓨틱스 컴퍼니 리미티드 | Lpa 억제제 및 이의 용도 |
CA3232420A1 (fr) | 2021-09-20 | 2023-03-23 | Alnylam Pharmaceuticals, Inc. | Compositions modulatrices de la sous-unite beta e de l'inhibine (inhbe) et leurs procedes d'utilisation |
CA3228838A1 (fr) * | 2021-09-23 | 2023-03-30 | Shanghai Argo Biopharmaceutical Co., Ltd. | Agregats de ligands multivalents avec echafaudage de diamine pour l'administration ciblee d'agents therapeutiques |
CA3233755A1 (fr) | 2021-10-01 | 2023-04-06 | Adarx Pharmaceuticals, Inc. | Compositions de modulation de la prekallicreine et leurs procedes d'utilisation |
WO2023069603A1 (fr) | 2021-10-22 | 2023-04-27 | Korro Bio, Inc. | Procédés et compositions pour perturber l'interaction de la protéine nrf2-keap1 par l'édition d'arn à médiation adar |
AU2022378567A1 (en) | 2021-10-29 | 2024-04-11 | Alnylam Pharmaceuticals, Inc. | Complement factor b (cfb) irna compositions and methods of use thereof |
WO2023076450A2 (fr) | 2021-10-29 | 2023-05-04 | Alnylam Pharmaceuticals, Inc. | Compositions d'agent d'arni de la huntingtine (htt) et leurs procédés d'utilisation |
WO2023083906A2 (fr) | 2021-11-11 | 2023-05-19 | F. Hoffmann-La Roche Ag | Combinaisons pharmaceutiques pour le traitement du vhb |
CA3241316A1 (fr) * | 2021-12-03 | 2023-06-08 | Quralis Corporation | Oligonucleotides antisens gapmeres avec des produits chimiques de squelette modifies |
GB202117758D0 (en) | 2021-12-09 | 2022-01-26 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
TW202333751A (zh) * | 2021-12-16 | 2023-09-01 | 大陸商上海拓界生物醫藥科技有限公司 | 一種dsrna、其製備方法及應用 |
CN118076738A (zh) * | 2021-12-16 | 2024-05-24 | 上海拓界生物医药科技有限公司 | 靶向LPA的siRNA及缀合物 |
WO2023111210A1 (fr) | 2021-12-17 | 2023-06-22 | F. Hoffmann-La Roche Ag | Combinaison d'oligonucléotides pour moduler rtel1 et fubp1 |
WO2023138659A1 (fr) * | 2022-01-20 | 2023-07-27 | 上海拓界生物医药科技有限公司 | Arn double brin, son utilisation et son procédé de préparation |
TW202345865A (zh) * | 2022-01-24 | 2023-12-01 | 大陸商上海舶望製藥有限公司 | 抑制LPA(Apo(a))蛋白表達的組合物和方法 |
WO2023141314A2 (fr) | 2022-01-24 | 2023-07-27 | Alnylam Pharmaceuticals, Inc. | Compositions d'agent d'arni d'enzyme de voie de biosynthèse de sulfate d'héparine et leurs méthodes d'utilisation |
CN117756866A (zh) * | 2022-01-30 | 2024-03-26 | 大睿生物医药科技(上海)有限公司 | 含有n-乙酰半乳糖胺的靶向配体 |
AR128558A1 (es) | 2022-02-21 | 2024-05-22 | Hoffmann La Roche | Oligonucleótido antisentido |
CN114703184B (zh) * | 2022-03-11 | 2024-06-18 | 厦门甘宝利生物医药有限公司 | Lpa抑制剂及其用途 |
US11879125B2 (en) | 2022-03-16 | 2024-01-23 | Empirico Inc. | GalNAc compositions for improving siRNA bioavailability |
CN115028670B (zh) * | 2022-06-24 | 2023-07-28 | 四川大学华西医院 | 一种n-乙酰基-d-半乳糖胺三聚体前体的制备方法 |
WO2024001172A1 (fr) * | 2022-06-27 | 2024-01-04 | Ractigen Therapeutics | Modulateurs oligonucléotidiques activant l'expression du facteur h du complément |
WO2024013361A1 (fr) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Oligonucléotides pour édition d'arn médiée par adar et leur utilisation |
WO2024013360A1 (fr) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Oligonucléotides chimiquement modifiés pour édition d'arn médiée par adar |
CN116814621A (zh) * | 2022-08-05 | 2023-09-29 | 厦门甘宝利生物医药有限公司 | 一种抑制apoc3基因表达的rna抑制剂及其应用 |
WO2024039776A2 (fr) | 2022-08-18 | 2024-02-22 | Alnylam Pharmaceuticals, Inc. | Compositions d'arnsi universelles ne ciblant pas et procédés d'utilisation associés |
TW202424193A (zh) | 2022-09-15 | 2024-06-16 | 美商艾拉倫製藥股份有限公司 | 第13型17β-羥基類固醇去氫酶(HSD17B13)iRNA組成物及其使用方法 |
WO2024098061A2 (fr) | 2022-11-04 | 2024-05-10 | Genkardia Inc. | Agents thérapeutiques à base d'oligonucléotides ciblant la cycline d2 pour le traitement d'une insuffisance cardiaque |
WO2024108217A1 (fr) | 2022-11-18 | 2024-05-23 | Genkardia Inc. | Méthodes et compositions pour prévenir, traiter ou inverser un dysfonctionnement diastolique cardiaque |
WO2024106539A1 (fr) * | 2022-11-18 | 2024-05-23 | 株式会社ボナック | Substance conjuguée à un ligand, acide nucléique la contenant et utilisation associée |
WO2024112937A2 (fr) * | 2022-11-23 | 2024-05-30 | Pretzel Therapeutics, Inc. | Compositions et méthodes de traitement du cancer et de maladies métaboliques |
WO2024114776A1 (fr) * | 2022-12-02 | 2024-06-06 | 上海舶望制药有限公司 | Analogues d'acides nucléiques abasiques bicycliques et composés oligomères préparés à partir de ceux-ci |
WO2024137729A1 (fr) * | 2022-12-21 | 2024-06-27 | Eli Lilly And Company | Nouveaux agents thérapeutiques à base d'arni de fas et leurs utilisations |
WO2024149282A1 (fr) * | 2023-01-10 | 2024-07-18 | Ausperbio Therapeutics Inc. | Oligonucléotides antisens multi-segmentés modifiés pour l'utilisation |
WO2024168010A2 (fr) | 2023-02-09 | 2024-08-15 | Alnylam Pharmaceuticals, Inc. | Molécules de reversir et leurs procédés d'utilisation |
WO2024175113A1 (fr) * | 2023-02-24 | 2024-08-29 | 南京明德新药研发有限公司 | Analogues d'arnsi double brin comprenant r et e et leurs conjugués |
CN116925160B (zh) * | 2023-09-15 | 2023-12-08 | 天津全和诚科技有限责任公司 | 一种GalNAc含糖环中间体及其制备方法 |
CN117568313B (zh) * | 2024-01-15 | 2024-04-26 | 上海贝斯昂科生物科技有限公司 | 基因编辑组合物及其用途 |
CN118146284B (zh) * | 2024-05-08 | 2024-07-26 | 北京悦康科创医药科技股份有限公司 | 一种GalNAc化合物、其与寡核苷酸缀合物及制备方法 |
Family Cites Families (379)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US5132418A (en) | 1980-02-29 | 1992-07-21 | University Patents, Inc. | Process for preparing polynucleotides |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
US4476301A (en) | 1982-04-29 | 1984-10-09 | Centre National De La Recherche Scientifique | Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon |
DE3329892A1 (de) | 1983-08-18 | 1985-03-07 | Köster, Hubert, Prof. Dr., 2000 Hamburg | Verfahren zur herstellung von oligonucleotiden |
US5118800A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
USRE34036E (en) | 1984-06-06 | 1992-08-18 | National Research Development Corporation | Data transmission using a transparent tone-in band system |
US5550111A (en) | 1984-07-11 | 1996-08-27 | Temple University-Of The Commonwealth System Of Higher Education | Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof |
FR2567892B1 (fr) | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
US5367066A (en) | 1984-10-16 | 1994-11-22 | Chiron Corporation | Oligonucleotides with selectably cleavable and/or abasic sites |
FR2575751B1 (fr) | 1985-01-08 | 1987-04-03 | Pasteur Institut | Nouveaux nucleosides de derives de l'adenosine, leur preparation et leurs applications biologiques |
US4751219A (en) | 1985-02-05 | 1988-06-14 | Nederlandse Centrale Organisatie Voor Toegepast-Natuur-Wetenschappelijk Onderzoek | Synthetic glycolipides, a process for the preparation thereof and several uses for these synthetic glycolipides |
US5235033A (en) | 1985-03-15 | 1993-08-10 | Anti-Gene Development Group | Alpha-morpholino ribonucleoside derivatives and polymers thereof |
US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
US5405938A (en) | 1989-12-20 | 1995-04-11 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
US5506337A (en) | 1985-03-15 | 1996-04-09 | Antivirals Inc. | Morpholino-subunit combinatorial library and method |
US5166315A (en) | 1989-12-20 | 1992-11-24 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
EP0260032B1 (fr) | 1986-09-08 | 1994-01-26 | Ajinomoto Co., Inc. | Composés pour cliver l'ARN dans une position spécifique, oligomères utilisés pour la préparation de ces composés et produits de départ pour la synthèse de ces oligomères |
US5264423A (en) | 1987-03-25 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US5276019A (en) | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
GB8712540D0 (en) * | 1987-05-28 | 1987-07-01 | Ucb Sa | Expression of human proapolipoprotein a-i |
JP2828642B2 (ja) | 1987-06-24 | 1998-11-25 | ハワード フローレイ インスティテュト オブ イクスペリメンタル フィジオロジー アンド メディシン | ヌクレオシド誘導体 |
US4924624A (en) | 1987-10-22 | 1990-05-15 | Temple University-Of The Commonwealth System Of Higher Education | 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof |
US5188897A (en) | 1987-10-22 | 1993-02-23 | Temple University Of The Commonwealth System Of Higher Education | Encapsulated 2',5'-phosphorothioate oligoadenylates |
ATE151467T1 (de) | 1987-11-30 | 1997-04-15 | Univ Iowa Res Found | Durch modifikationen an der 3'-terminalen phosphodiesterbindung stabilisierte dna moleküle, ihre verwendung als nukleinsäuresonden sowie als therapeutische mittel zur hemmung der expression spezifischer zielgene |
US5403711A (en) | 1987-11-30 | 1995-04-04 | University Of Iowa Research Foundation | Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled nucleic acid probe is cleaved |
WO1989009221A1 (fr) | 1988-03-25 | 1989-10-05 | University Of Virginia Alumni Patents Foundation | N-alkylphosphoramidates oligonucleotides |
US5278302A (en) | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
US5216141A (en) | 1988-06-06 | 1993-06-01 | Benner Steven A | Oligonucleotide analogs containing sulfur linkages |
US5175273A (en) | 1988-07-01 | 1992-12-29 | Genentech, Inc. | Nucleic acid intercalating agents |
US5194599A (en) | 1988-09-23 | 1993-03-16 | Gilead Sciences, Inc. | Hydrogen phosphonodithioate compositions |
US5256775A (en) | 1989-06-05 | 1993-10-26 | Gilead Sciences, Inc. | Exonuclease-resistant oligonucleotides |
US5134066A (en) | 1989-08-29 | 1992-07-28 | Monsanto Company | Improved probes using nucleosides containing 3-dezauracil analogs |
US5591722A (en) | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
US5399676A (en) | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5721218A (en) | 1989-10-23 | 1998-02-24 | Gilead Sciences, Inc. | Oligonucleotides with inverted polarity |
ATE269870T1 (de) | 1989-10-24 | 2004-07-15 | Isis Pharmaceuticals Inc | 2'-modifizierte oligonukleotide |
US5264564A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences | Oligonucleotide analogs with novel linkages |
US5264562A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences, Inc. | Oligonucleotide analogs with novel linkages |
US5177198A (en) | 1989-11-30 | 1993-01-05 | University Of N.C. At Chapel Hill | Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates |
US5130302A (en) | 1989-12-20 | 1992-07-14 | Boron Bilogicals, Inc. | Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same |
US5623065A (en) | 1990-08-13 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Gapped 2' modified oligonucleotides |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5646265A (en) | 1990-01-11 | 1997-07-08 | Isis Pharmceuticals, Inc. | Process for the preparation of 2'-O-alkyl purine phosphoramidites |
US5681941A (en) | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
US5587470A (en) | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
US5457191A (en) | 1990-01-11 | 1995-10-10 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
US7101993B1 (en) | 1990-01-11 | 2006-09-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides containing 2′-O-modified purines |
US6005087A (en) | 1995-06-06 | 1999-12-21 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
US5670633A (en) | 1990-01-11 | 1997-09-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
US5459255A (en) | 1990-01-11 | 1995-10-17 | Isis Pharmaceuticals, Inc. | N-2 substituted purines |
US5859221A (en) | 1990-01-11 | 1999-01-12 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
US5220007A (en) | 1990-02-15 | 1993-06-15 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of RNA and production of encoded polypeptides |
US5149797A (en) | 1990-02-15 | 1992-09-22 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of rna and production of encoded polypeptides |
US5321131A (en) | 1990-03-08 | 1994-06-14 | Hybridon, Inc. | Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling |
US5470967A (en) | 1990-04-10 | 1995-11-28 | The Dupont Merck Pharmaceutical Company | Oligonucleotide analogs with sulfamate linkages |
GB9009980D0 (en) | 1990-05-03 | 1990-06-27 | Amersham Int Plc | Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides |
EP0745689A3 (fr) | 1990-05-11 | 1996-12-11 | Microprobe Corporation | Bâtonnet d'hybridation d'acide nucléique |
US5378825A (en) | 1990-07-27 | 1995-01-03 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs |
US5623070A (en) | 1990-07-27 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
BR9106702A (pt) | 1990-07-27 | 1993-06-08 | Isis Pharmaceuticals Inc | Analogo de oligonucleotideos e processos para modular a producao de uma proteina por um organismo e para tratar um organismo |
US5541307A (en) | 1990-07-27 | 1996-07-30 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs and solid phase synthesis thereof |
US5608046A (en) | 1990-07-27 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Conjugated 4'-desmethyl nucleoside analog compounds |
US5618704A (en) | 1990-07-27 | 1997-04-08 | Isis Pharmacueticals, Inc. | Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling |
US5602240A (en) | 1990-07-27 | 1997-02-11 | Ciba Geigy Ag. | Backbone modified oligonucleotide analogs |
US5489677A (en) | 1990-07-27 | 1996-02-06 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms |
US5386023A (en) | 1990-07-27 | 1995-01-31 | Isis Pharmaceuticals | Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling |
US5677437A (en) | 1990-07-27 | 1997-10-14 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
US5610289A (en) | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
US5223618A (en) | 1990-08-13 | 1993-06-29 | Isis Pharmaceuticals, Inc. | 4'-desmethyl nucleoside analog compounds |
BR9106729A (pt) | 1990-08-03 | 1993-07-20 | Sterling Winthrop Inc | Composto,processos para inibir a degradacao por nuclease de compostos e para estabilizar sequencias de nicleotideos ou oligonucleosideos,composicao utilizavel para inibir expressao de genes e processo para inibir expressao de genes em um mamifero necessitando de tal tratamento |
US5177196A (en) | 1990-08-16 | 1993-01-05 | Microprobe Corporation | Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof |
US5214134A (en) | 1990-09-12 | 1993-05-25 | Sterling Winthrop Inc. | Process of linking nucleosides with a siloxane bridge |
US5561225A (en) | 1990-09-19 | 1996-10-01 | Southern Research Institute | Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages |
JPH06505704A (ja) | 1990-09-20 | 1994-06-30 | ギリアド サイエンシズ,インコーポレイテッド | 改変ヌクレオシド間結合 |
US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
US6582908B2 (en) | 1990-12-06 | 2003-06-24 | Affymetrix, Inc. | Oligonucleotides |
US5948903A (en) | 1991-01-11 | 1999-09-07 | Isis Pharmaceuticals, Inc. | Synthesis of 3-deazapurines |
US5672697A (en) | 1991-02-08 | 1997-09-30 | Gilead Sciences, Inc. | Nucleoside 5'-methylene phosphonates |
US7015315B1 (en) | 1991-12-24 | 2006-03-21 | Isis Pharmaceuticals, Inc. | Gapped oligonucleotides |
US5571799A (en) | 1991-08-12 | 1996-11-05 | Basco, Ltd. | (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response |
EP0538194B1 (fr) | 1991-10-17 | 1997-06-04 | Novartis AG | Nucléosides et oligonucléosides bicycliques, leur procédé de préparation et leurs intermédiaires |
US5594121A (en) | 1991-11-07 | 1997-01-14 | Gilead Sciences, Inc. | Enhanced triple-helix and double-helix formation with oligomers containing modified purines |
US5484908A (en) | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
TW393513B (en) | 1991-11-26 | 2000-06-11 | Isis Pharmaceuticals Inc | Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines |
CA2122365C (fr) | 1991-11-26 | 2010-05-11 | Brian Froehler | Formation amelioree a triple helice et double helice avec oligomeres renfermant des pyrimidines modifiees |
US5792608A (en) | 1991-12-12 | 1998-08-11 | Gilead Sciences, Inc. | Nuclease stable and binding competent oligomers and methods for their use |
US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
ATE204879T1 (de) * | 1991-12-24 | 2001-09-15 | Isis Pharmaceuticals Inc | Antisense oligonukleotide |
US5700922A (en) | 1991-12-24 | 1997-12-23 | Isis Pharmaceuticals, Inc. | PNA-DNA-PNA chimeric macromolecules |
FR2687679B1 (fr) | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
US5633360A (en) | 1992-04-14 | 1997-05-27 | Gilead Sciences, Inc. | Oligonucleotide analogs capable of passive cell membrane permeation |
US5434257A (en) | 1992-06-01 | 1995-07-18 | Gilead Sciences, Inc. | Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages |
EP0577558A2 (fr) | 1992-07-01 | 1994-01-05 | Ciba-Geigy Ag | Nucléosides carbocycliques contenant des noyaux bicycliques, oligonucléotides en dérivant, procédé pour leur préparation, leur application et des intermédiaires |
US5652355A (en) | 1992-07-23 | 1997-07-29 | Worcester Foundation For Experimental Biology | Hybrid oligonucleotide phosphorothioates |
CA2140542A1 (fr) | 1992-07-27 | 1994-02-03 | Abeysingle Padmapriya | Alkylphosphonothioates d'oligonucleotides |
EP0673559A1 (fr) | 1992-12-14 | 1995-09-27 | Honeywell Inc. | Systeme de moteur a tolerance de pannes |
DE69400208T2 (de) | 1993-01-25 | 1996-11-28 | Hybridon Inc | Olionukleotidalkylphosphonate und -phosphonothioate |
US5476925A (en) | 1993-02-01 | 1995-12-19 | Northwestern University | Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups |
GB9304618D0 (en) | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Chemical compounds |
GB9304620D0 (en) | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Compounds |
DK0691968T3 (da) | 1993-03-30 | 1998-02-23 | Sanofi Sa | Acykliske nukleosid-analoge og oligonukleotidsekvenser indeholdende disse |
HU9501974D0 (en) | 1993-03-31 | 1995-09-28 | Sterling Winthrop Inc | Oligonucleotides with amide linkages replacing phosphodiester linkages |
US5502177A (en) | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
US5801154A (en) | 1993-10-18 | 1998-09-01 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of multidrug resistance-associated protein |
US5457187A (en) | 1993-12-08 | 1995-10-10 | Board Of Regents University Of Nebraska | Oligonucleotides containing 5-fluorouracil |
US5446137B1 (en) | 1993-12-09 | 1998-10-06 | Behringwerke Ag | Oligonucleotides containing 4'-substituted nucleotides |
WO1995015972A1 (fr) | 1993-12-09 | 1995-06-15 | Thomas Jefferson University | Composes et procedes pour realiser des mutations dirigees sur le site dans des cellules eucaryotes |
US5519134A (en) | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
US5728518A (en) | 1994-01-12 | 1998-03-17 | The Immune Response Corporation | Antiviral poly-and oligonucleotides |
US5596091A (en) | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
US5627053A (en) | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
US5625050A (en) | 1994-03-31 | 1997-04-29 | Amgen Inc. | Modified oligonucleotides and intermediates useful in nucleic acid therapeutics |
US5646269A (en) | 1994-04-28 | 1997-07-08 | Gilead Sciences, Inc. | Method for oligonucleotide analog synthesis |
US5525711A (en) | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
US5597909A (en) | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
US5599706A (en) | 1994-09-23 | 1997-02-04 | Stinchcomb; Dan T. | Ribozymes targeted to apo(a) mRNA |
US5681940A (en) | 1994-11-02 | 1997-10-28 | Icn Pharmaceuticals | Sugar modified nucleosides and oligonucleotides |
US6172045B1 (en) | 1994-12-07 | 2001-01-09 | Neorx Corporation | Cluster clearing agents |
US6908903B1 (en) | 1994-12-07 | 2005-06-21 | Aletheon Pharmaceuticals, Inc. | Cluster clearing agents |
US5652356A (en) | 1995-08-17 | 1997-07-29 | Hybridon, Inc. | Inverted chimeric and hybrid oligonucleotides |
JP2000501414A (ja) | 1995-11-22 | 2000-02-08 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 生体分子の細胞取り込みを高めるリガンド |
US20030119724A1 (en) | 1995-11-22 | 2003-06-26 | Ts`O Paul O.P. | Ligands to enhance cellular uptake of biomolecules |
US5998203A (en) | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
US7875733B2 (en) | 2003-09-18 | 2011-01-25 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation |
WO1998013381A1 (fr) | 1996-09-26 | 1998-04-02 | Ajinomoto Co., Inc. | Proteines modifiees physiologiquement actives et compositions medicamenteuses les contenant |
USRE44779E1 (en) | 1997-03-07 | 2014-02-25 | Santaris Pharma A/S | Bicyclonucleoside and oligonucleotide analogues |
JP3756313B2 (ja) | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
US6770748B2 (en) | 1997-03-07 | 2004-08-03 | Takeshi Imanishi | Bicyclonucleoside and oligonucleotide analogue |
DE04020014T1 (de) | 1997-09-12 | 2006-01-26 | Exiqon A/S | Bi-zyklische - Nukleosid,Nnukleotid und Oligonukleotid-Analoga |
US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
US7572582B2 (en) | 1997-09-12 | 2009-08-11 | Exiqon A/S | Oligonucleotide analogues |
US20040171564A1 (en) | 1997-11-20 | 2004-09-02 | Honkanen Richard E. | Antisense oligonucleotide modulation of human serine/threonine protein phosphatase gene expression |
US20030228597A1 (en) | 1998-04-13 | 2003-12-11 | Cowsert Lex M. | Identification of genetic targets for modulation by oligonucleotides and generation of oligonucleotides for gene modulation |
US6300319B1 (en) | 1998-06-16 | 2001-10-09 | Isis Pharmaceuticals, Inc. | Targeted oligonucleotide conjugates |
US6043352A (en) | 1998-08-07 | 2000-03-28 | Isis Pharmaceuticals, Inc. | 2'-O-Dimethylaminoethyloxyethyl-modified oligonucleotides |
RU2249463C2 (ru) * | 1998-08-19 | 2005-04-10 | Бакстер Хелфкэа С.А. | Иммуногенный конъюгат бета-пропионамид-связанного полисахарида с белком, использующийся в качестве вакцины |
CA2340692A1 (fr) | 1998-08-19 | 2000-03-02 | North American Vaccine, Inc. | Conjugue de proteine-polysaccharide immunogene a liaison beta-propionamido, utile comme vaccin etabli au moyen d'un polysaccharide n-acryloyle |
US6166239A (en) | 1998-09-04 | 2000-12-26 | Isis Pharmaceuticals, Inc. | Oligonucleotide protecting groups |
BRPI0008131B8 (pt) | 1999-02-12 | 2021-05-25 | Daiichi Sankyo Co Ltd | composto ou um sal deste, análogo de oligonucleotídeo, composição farmacêutica, sonda para um gene,iniciador para começar a amplificação, uso de um análogo de oligonucleotídeo ou de um sal deste farmacologicamente aceitável, agente antisentido, e, agente antígeno |
US20030170249A1 (en) | 1999-02-19 | 2003-09-11 | Hakomori Sen-Itiroh | Vaccines directed to cancer-associated carbohydrate antigens |
US7084125B2 (en) | 1999-03-18 | 2006-08-01 | Exiqon A/S | Xylo-LNA analogues |
US7098192B2 (en) * | 1999-04-08 | 2006-08-29 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of STAT3 expression |
US6159694A (en) | 1999-04-08 | 2000-12-12 | Isis Pharmaceuticals Inc. | Antisense modulation of stat3 expression |
EP2363478B1 (fr) | 1999-04-21 | 2019-07-24 | Alnylam Pharmaceuticals, Inc. | Procédés et compositions pour inhiber la fonction de séquences de polynucléotides |
PT1178999E (pt) | 1999-05-04 | 2007-06-26 | Santaris Pharma As | Análogos de l-ribo-lna |
US6525191B1 (en) | 1999-05-11 | 2003-02-25 | Kanda S. Ramasamy | Conformationally constrained L-nucleosides |
US6383812B1 (en) | 1999-05-28 | 2002-05-07 | Academia Sinica | Anti liver disease drug R-YEEE and method of synthesizing branched galactose-terminal glycoproteins |
US20080281041A1 (en) | 1999-06-07 | 2008-11-13 | Rozema David B | Reversibly Masked Polymers |
US8541548B2 (en) | 1999-06-07 | 2013-09-24 | Arrowhead Madison Inc. | Compounds and methods for reversible modification of biologically active molecules |
US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
CA2379152A1 (fr) | 1999-07-16 | 2001-01-25 | Hyseq, Inc. | Nouveaux procedes et materiaux des angiopoietines |
JP4151751B2 (ja) | 1999-07-22 | 2008-09-17 | 第一三共株式会社 | 新規ビシクロヌクレオシド類縁体 |
DE19935303A1 (de) | 1999-07-28 | 2001-02-08 | Aventis Pharma Gmbh | Oligonukleotide zur Inhibierung der Expression von humanem eg5 |
US20020082227A1 (en) | 1999-09-30 | 2002-06-27 | Scott Henry | Use of oligonucleotides for inhibition of complement activation |
US20050112118A1 (en) | 1999-12-02 | 2005-05-26 | Myriad Genetics, Incorporated | Compositions and methods for treating inflammatory disorders |
PL355666A1 (en) | 1999-12-09 | 2004-05-04 | Sankyo Company, Limited | Method of testing remedy or preventive for hyperlipemia |
EP1244667B1 (fr) | 1999-12-30 | 2006-04-05 | K.U. Leuven Research & Development | Acides nucleiques contenant cyclohexene |
US7179796B2 (en) | 2000-01-18 | 2007-02-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
US20020055479A1 (en) | 2000-01-18 | 2002-05-09 | Cowsert Lex M. | Antisense modulation of PTP1B expression |
US6602857B1 (en) | 2000-01-18 | 2003-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
US6261840B1 (en) | 2000-01-18 | 2001-07-17 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
US8202979B2 (en) | 2002-02-20 | 2012-06-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
US7491805B2 (en) | 2001-05-18 | 2009-02-17 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
WO2001060860A2 (fr) | 2000-02-17 | 2001-08-23 | Millennium Predictive Medicine, Inc. | Genes, compositions, kits, et procedes d'identification, d'evaluation, de prevention, et de traitement du cancer de la prostate |
AU2001282522A1 (en) | 2000-08-29 | 2002-03-13 | Takeshi Imanishi | Novel nucleoside analogs and oligonucleotide derivatives containing these analogs |
US6426220B1 (en) | 2000-10-30 | 2002-07-30 | Isis Pharmaceuticals, Inc. | Antisense modulation of calreticulin expression |
JP2004536027A (ja) | 2000-12-01 | 2004-12-02 | ジョーンズ・ホプキンス・ユニーバーシティー | グリコシル化/ガラクトシル化ペプチドの接合体、二官能性リンカー、およびヌクレオチドのモノマー/ポリマー、および関連する組成物および使用方法 |
WO2002087541A1 (fr) | 2001-04-30 | 2002-11-07 | Protiva Biotherapeutics Inc. | Formulations a base de lipides pour transfert genique |
CA2450022A1 (fr) | 2001-06-08 | 2002-12-19 | Sankyo Company, Limited | Procede de test de medicament destine a traiter ou a prevenir des maladies telles que l'hyperlipemie |
US20030158403A1 (en) | 2001-07-03 | 2003-08-21 | Isis Pharmaceuticals, Inc. | Nuclease resistant chimeric oligonucleotides |
CA2452458A1 (fr) | 2001-07-03 | 2003-01-16 | Isis Pharmaceuticals, Inc. | Oligonucleotides chimeres resistants a la nuclease |
US20030175906A1 (en) | 2001-07-03 | 2003-09-18 | Muthiah Manoharan | Nuclease resistant chimeric oligonucleotides |
US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
US6964950B2 (en) | 2001-07-25 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of C-reactive protein expression |
US7259150B2 (en) | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
WO2003014397A1 (fr) | 2001-08-09 | 2003-02-20 | Biomedlab Corporation | Sonde destinee a la detection de virus enteriques, kit de detection et procede de detection de virus enteriques |
EP1446412B1 (fr) | 2001-09-04 | 2012-03-07 | Exiqon A/S | Compositions d'acides nucleiques verrouilles et utilisations |
US7439043B2 (en) | 2001-10-10 | 2008-10-21 | Neose Technologies, Inc. | Galactosyl nucleotide sugars |
KR101012904B1 (ko) | 2001-11-16 | 2011-02-08 | 제넨테크, 인크. | 안지오포이에틴-유사 단백질 3 angptl3을 함유하는조성물 및 이를 사용하는 방법 |
US20100240730A1 (en) | 2002-02-20 | 2010-09-23 | Merck Sharp And Dohme Corp. | RNA Interference Mediated Inhibition of Gene Expression Using Chemically Modified Short Interfering Nucleic Acid (siNA) |
AU2003274906A1 (en) | 2002-07-31 | 2004-02-16 | Nucleonics, Inc. | Double stranded rna structures and constructs, and methods for generating and using the same |
WO2004014933A1 (fr) | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions pour l'interference de l'arn et procedes d'utilisation |
WO2004024757A2 (fr) | 2002-09-11 | 2004-03-25 | Santaris Pharma A/S | Molecules pna modifiées |
US20060035344A1 (en) | 2002-10-18 | 2006-02-16 | Pachuk Catherine J | Double-stranded rna structures and constructs, and methods for generating and using the same |
WO2004042029A2 (fr) | 2002-11-05 | 2004-05-21 | Isis Pharmaceuticals, Inc. | Compositions oligomeres possedant des bases modifiees destinees a se lier a la cytosine, l'uracile ou la thymine et leur utilisation dans la modulation genique |
EP1562971B1 (fr) | 2002-11-05 | 2014-02-12 | Isis Pharmaceuticals, Inc. | Composes oligomeres renfermant un substitut de sucre polycyclique et compositions intervenant dans la modulation genique |
US7511131B2 (en) | 2002-11-13 | 2009-03-31 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
US20060009410A1 (en) | 2002-11-13 | 2006-01-12 | Crooke Rosanne M | Effects of apolipoprotein B inhibition on gene expression profiles in animals |
EP1569695B1 (fr) | 2002-11-13 | 2013-05-15 | Genzyme Corporation | Modulation antisens de l'expression d'apolipoproteine b |
PT2284266E (pt) | 2002-11-14 | 2013-12-17 | Thermo Fisher Scient Biosciences Inc | Siarn contra tp53 |
CA2936612C (fr) | 2002-12-20 | 2017-11-21 | Celera Corporation | Polymorphismes atf6 associes a une infarctus du myocarde, methode de detection et utilisations associees |
US6673661B1 (en) | 2002-12-20 | 2004-01-06 | Taiwan Semiconductor Manufacturing Co., Ltd. | Self-aligned method for forming dual gate thin film transistor (TFT) device |
JP4152955B2 (ja) | 2003-01-09 | 2008-09-17 | ポステック・ファウンデーション | 新規フォスフォアミダイト化合物 |
WO2004072046A2 (fr) | 2003-02-12 | 2004-08-26 | Carex S.A. | Modulation de l'activite des recepteurs nucleaires |
US7803781B2 (en) | 2003-02-28 | 2010-09-28 | Isis Pharmaceuticals, Inc. | Modulation of growth hormone receptor expression and insulin-like growth factor expression |
WO2004090108A2 (fr) * | 2003-04-03 | 2004-10-21 | Alnylam Pharmaceuticals | Conjugues d'arni |
EP2239329A1 (fr) | 2003-03-07 | 2010-10-13 | Alnylam Pharmaceuticals, Inc. | Compositions thérapeutiques |
US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
US7851615B2 (en) | 2003-04-17 | 2010-12-14 | Alnylam Pharmaceuticals, Inc. | Lipophilic conjugated iRNA agents |
US7723509B2 (en) | 2003-04-17 | 2010-05-25 | Alnylam Pharmaceuticals | IRNA agents with biocleavable tethers |
EP1620544B1 (fr) | 2003-04-17 | 2018-09-19 | Alnylam Pharmaceuticals Inc. | Agents modifies d'arni |
US7750142B2 (en) | 2003-04-28 | 2010-07-06 | Isis Pharmaceuticals, Inc. | Modulation of glucagon receptor expression |
US7399853B2 (en) | 2003-04-28 | 2008-07-15 | Isis Pharmaceuticals | Modulation of glucagon receptor expression |
WO2004101619A1 (fr) | 2003-05-15 | 2004-11-25 | Shionogi Co., Ltd. | Conception rationnelle et synthese de glycopeptide fonctionnel |
WO2004106356A1 (fr) | 2003-05-27 | 2004-12-09 | Syddansk Universitet | Derives de nucleotides fonctionnalises |
ATE555118T1 (de) | 2003-08-28 | 2012-05-15 | Takeshi Imanishi | Neue synthetische nukleidsäuren vom typ mit quervernetzter n-o-bindung |
CN100558893C (zh) | 2003-09-18 | 2009-11-11 | Isis药物公司 | eIF4E表达的调节 |
US8258105B2 (en) * | 2003-10-07 | 2012-09-04 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides optimized for kidney targeting |
US7959919B2 (en) | 2003-11-19 | 2011-06-14 | Novelmed Therapeutics, Inc. | Method of inhibiting factor B-mediated complement activation |
WO2005065686A1 (fr) | 2004-01-07 | 2005-07-21 | Adipogen Pharmaceuticals Pty Limited | Agents de modulation de la differenciation et utilisations associees |
US20050164271A1 (en) | 2004-01-20 | 2005-07-28 | Sanjay Bhanot | Modulation of glucocorticoid receptor expression |
JP4628960B2 (ja) * | 2004-02-05 | 2011-02-09 | 独立行政法人科学技術振興機構 | リンカー化合物及びリガンド複合体、並びにそれらの製造方法 |
US20050244869A1 (en) | 2004-04-05 | 2005-11-03 | Brown-Driver Vickie L | Modulation of transthyretin expression |
WO2005097155A1 (fr) | 2004-04-08 | 2005-10-20 | Takara Bio Inc. | Agent induisant un allongement de neurite |
KR20070085113A (ko) | 2004-05-11 | 2007-08-27 | 가부시키가이샤 알파젠 | Rna간섭을 생기게 하는 폴리뉴클레오티드, 및 이를 이용한유전자발현억제 방법 |
AU2005252662B2 (en) | 2004-06-03 | 2011-08-18 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
CN102641503A (zh) | 2004-07-20 | 2012-08-22 | 健泰科生物技术公司 | 血管生成素样4蛋白抑制剂,组合,以及其用途 |
DK1781698T3 (en) | 2004-07-20 | 2016-10-03 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE USE OF Angiopoietin-like-4-PROTEIN |
EP2997980B1 (fr) * | 2004-08-10 | 2017-12-20 | Kastle Therapeutics, LLC | Procédés de modulation des niveaux de lipoprotéine et cholestérol chez l'homme |
AU2005272816B2 (en) | 2004-08-10 | 2011-08-11 | Alnylam Pharmaceuticals, Inc. | Chemically modified oligonucleotides |
US20090203132A1 (en) | 2004-09-09 | 2009-08-13 | Swayze Eric E | Pyrrolidinyl groups for attaching conjugates to oligomeric compounds |
CA2582464A1 (fr) | 2004-10-13 | 2006-04-27 | Sanjay Bhanot | Modulation antisens de l'expression de ptp1b |
EP1812569A2 (fr) | 2004-11-08 | 2007-08-01 | K.U. Leuven Research and Development | Nucleosides modifies pour interference arn |
US20060148740A1 (en) | 2005-01-05 | 2006-07-06 | Prosensa B.V. | Mannose-6-phosphate receptor mediated gene transfer into muscle cells |
JP2008527993A (ja) | 2005-01-24 | 2008-07-31 | アヴァリス・アクチエボラーグ | 特異性及び送達の改善のためのsiRNA分子、shRNA分子又はアンチセンス分子及び機能的実体を含む複合体 |
US20090118213A1 (en) * | 2005-09-15 | 2009-05-07 | Henrik Frydenlund Hansen | Rna antagonist compounds for the inhibition of apo-b100 expression |
JP2009508527A (ja) | 2005-09-19 | 2009-03-05 | ジヨンソン・アンド・ジヨンソン・フアーマシユーチカル・リサーチ・アンド・デベロツプメント・エルエルシー | グルココルチコイド受容体発現の調節 |
EA200800869A1 (ru) | 2005-09-19 | 2008-10-30 | ДЖОНСОН ЭНД ДЖОНСОН ФАРМАСЬЮТИКАЛ РИСЕРЧ ЭНД ДИВЕЛОПМЕНТ, Эл. Эл. Си. | Модуляция экспрессии рецептора глюкагона |
EP2422819B1 (fr) | 2006-01-26 | 2017-03-01 | Ionis Pharmaceuticals, Inc. | Compositions et leurs utilisations dirigées vers l'huntingtine |
US7569686B1 (en) | 2006-01-27 | 2009-08-04 | Isis Pharmaceuticals, Inc. | Compounds and methods for synthesis of bicyclic nucleic acid analogs |
PL1984381T3 (pl) | 2006-01-27 | 2011-03-31 | Isis Pharmaceuticals Inc | Zmodyfikowane w pozycji 6 analogi bicykliczne kwasów nukleinowych |
EP2015758B1 (fr) | 2006-05-05 | 2014-04-02 | Isis Pharmaceuticals, Inc. | Composés et procédés permettant de moduler l'expression de la protéine apob |
ES2366973T3 (es) * | 2006-05-05 | 2011-10-27 | Isis Pharmaceuticals, Inc. | Compuestos y procedimiento para modular la expresión génica. |
US7547684B2 (en) | 2006-05-11 | 2009-06-16 | Isis Pharmaceuticals, Inc. | 5′-modified bicyclic nucleic acid analogs |
US7666854B2 (en) | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
US8101585B2 (en) | 2006-08-04 | 2012-01-24 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of JNK proteins |
US8658211B2 (en) | 2006-08-18 | 2014-02-25 | Arrowhead Madison Inc. | Polyconjugates for in vivo delivery of polynucleotides |
CA2660842C (fr) | 2006-08-18 | 2012-03-13 | F. Hoffmann-La Roche Ag | Polyconjugues pour l'administration in vivo de polynucleotides |
EP2081949B1 (fr) | 2006-09-22 | 2014-12-10 | GE Healthcare Dharmacon, Inc. | Complexes d'oligonucléotides tripartites et procédés de silençage de gènes par interférence arn |
ATE540118T1 (de) | 2006-10-18 | 2012-01-15 | Isis Pharmaceuticals Inc | Antisense-verbindungen |
KR20090103894A (ko) | 2006-11-27 | 2009-10-01 | 아이시스 파마수티컬즈 인코포레이티드 | 고콜레스테롤혈증을 치료하는 방법 |
US8093222B2 (en) | 2006-11-27 | 2012-01-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
PT2121751T (pt) | 2006-12-08 | 2017-04-18 | Lexicon Pharmaceuticals Inc | Anticorpos monoclonais contra angptl3 |
CA2839162A1 (fr) * | 2006-12-20 | 2008-06-26 | Xoma Technology Ltd. | Methodes de traitement de maladies associees a l'interleukine-1-.beta. |
US20100190837A1 (en) | 2007-02-15 | 2010-07-29 | Isis Pharmaceuticals, Inc. | 5'-Substituted-2-F' Modified Nucleosides and Oligomeric Compounds Prepared Therefrom |
WO2008098788A2 (fr) | 2007-02-16 | 2008-08-21 | Ktb Tumorforschungsgesellschaft Mbh | Récepteur et promédicament ciblé par l'antigène |
EP2134173A4 (fr) | 2007-03-01 | 2010-11-10 | Wellstat Ophthalmics Corp | Traitement de maladies caracterisees par une inflammation |
US20100055782A1 (en) | 2007-03-02 | 2010-03-04 | Mdrna, Inc. | Nucleic acid compounds for inhibiting myc gene expression and uses thereof |
AU2008242583B2 (en) | 2007-04-23 | 2013-10-10 | Alnylam Pharmaceuticals, Inc. | Glycoconjugates of RNA interference agents |
US8278425B2 (en) | 2007-05-30 | 2012-10-02 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
US8278426B2 (en) | 2007-06-08 | 2012-10-02 | Isis Pharmaceuticals, Inc. | Carbocyclic bicyclic nucleic acid analogs |
WO2009003009A1 (fr) | 2007-06-26 | 2008-12-31 | Enanta Pharmaceuticals, Inc. | Pyrrolidine substituée utilisée en tant qu'agent anti-infectieux |
WO2009006478A2 (fr) | 2007-07-05 | 2009-01-08 | Isis Pharmaceuticals, Inc. | Analogues d'acides nucléiques bicycliques disubstitués en position 6 |
CN101821277B (zh) | 2007-08-15 | 2014-05-07 | Isis制药公司 | 四氢吡喃核酸类似物 |
CA2696699A1 (fr) * | 2007-08-20 | 2009-02-26 | Protalix Ltd. | Conjugues de proteines contenant un saccharide et leurs utilisations |
MX2010003606A (es) * | 2007-10-01 | 2010-07-02 | Isis Pharmaceuticals Inc | Modulacion antisentido de la expresion del receptor del factor de crecimiento fibroblastico 4. |
WO2009061851A2 (fr) | 2007-11-09 | 2009-05-14 | Isis Pharmaceuticals, Inc. | Modulation de l'expression du facteur 7 |
WO2009067647A1 (fr) | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Analogues d'acide nucléique alpha-l-bicyclique carbocyclique |
US20090247608A1 (en) | 2007-12-04 | 2009-10-01 | Alnylam Pharmaceuticals, Inc. | Targeting Lipids |
JP4585611B2 (ja) | 2007-12-27 | 2010-11-24 | 株式会社ステリック再生医科学研究所 | 糖鎖関連遺伝子、およびその利用 |
CA2713379A1 (fr) | 2008-01-31 | 2009-11-05 | Alnylam Pharmaceuticals, Inc. | Procedes optimises d'administration d'arnds ciblant le gene pcsk9 |
WO2009100320A2 (fr) | 2008-02-07 | 2009-08-13 | Isis Pharmaceuticals, Inc. | Analogues d’acides nucléiques de cyclohexitol bicycliques |
US20110269814A1 (en) | 2008-03-26 | 2011-11-03 | Alnylam Pharamaceuticals, Inc. | 2'-f modified rna interference agents |
AU2009234266B2 (en) | 2008-04-11 | 2015-08-06 | Tekmira Pharmaceuticals Corporation | Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components |
WO2009143369A2 (fr) | 2008-05-22 | 2009-11-26 | Isis Pharmaceuticals, Inc. | Procédé de préparation de nucléosides et de leurs analogues sans utiliser de chromatographie |
WO2009148605A2 (fr) | 2008-06-04 | 2009-12-10 | Isis Pharmaceuticals, Inc. | Procédés pour traiter une hypercholestérolémie |
WO2010006215A1 (fr) | 2008-07-09 | 2010-01-14 | Celera Corporation | Polymorphismes génétiques associés à des maladies cardiovasculaires et procédés de détection et d'utilisation de ceux-ci |
WO2010017509A1 (fr) | 2008-08-07 | 2010-02-11 | Isis Pharmaceuticals, Inc. | Modulation de l'expression de transthyrétine pour le traitement de troubles concernant le système nerveux central (cns) |
US8962580B2 (en) | 2008-09-23 | 2015-02-24 | Alnylam Pharmaceuticals, Inc. | Chemical modifications of monomers and oligonucleotides with cycloaddition |
WO2010036698A1 (fr) | 2008-09-24 | 2010-04-01 | Isis Pharmaceuticals, Inc. | Nucléosides alpha-l-bicycliques substitués |
WO2010036696A1 (fr) | 2008-09-24 | 2010-04-01 | Isis Pharmaceuticals, Inc. | Analogues d'acide nucléique cyclohexényle |
CA2966011C (fr) | 2008-10-15 | 2021-10-19 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression du facteur 11 |
IL310600A (en) * | 2008-10-20 | 2024-04-01 | Alnylam Pharmaceuticals Inc | Compounds and methods for inhibiting transthyretin expression |
EP2358398A2 (fr) | 2008-10-24 | 2011-08-24 | Isis Pharmaceuticals, Inc. | Composés oligomères et méthodes |
AU2009308217B2 (en) | 2008-10-24 | 2016-01-21 | Ionis Pharmaceuticals, Inc. | 5' and 2' bis-substituted nucleosides and oligomeric compounds prepared therefrom |
WO2010054401A1 (fr) | 2008-11-10 | 2010-05-14 | Alnylam Pharmaceuticals, Inc. | Nouveaux lipides et nouvelles compositions pour l’administration d’agents thérapeutiques |
CA2750561C (fr) | 2009-01-26 | 2017-10-10 | Protiva Biotherapeutics, Inc. | Compositions et procedes d'inactivation de l'expression de l'apolipoproteine c-iii |
EP2391343B1 (fr) | 2009-01-29 | 2017-03-01 | Arbutus Biopharma Corporation | Préparation lipidique améliorée pour la delivrance d'acides nucleiques |
EP2403863B1 (fr) | 2009-03-02 | 2013-08-28 | Alnylam Pharmaceuticals Inc. | Modifications chimiques d'acide nucléique |
FR2943060B1 (fr) | 2009-03-13 | 2013-01-04 | Commissariat Energie Atomique | Agents chelatants d'ions metalliques, leurs procedes de preparation et leurs applications |
AU2010236286B2 (en) | 2009-04-15 | 2013-06-06 | Isis Pharmaceuticals, Inc. | Modulation of inflammatory responses by Factor XI |
CN105903022A (zh) * | 2009-05-05 | 2016-08-31 | 阿尔尼拉姆医药品有限公司 | 脂质组合物 |
JP5875976B2 (ja) | 2009-06-01 | 2016-03-02 | ヘイロー−バイオ アールエヌエーアイ セラピューティクス, インコーポレイテッド | 多価rna干渉のためのポリヌクレオチド、組成物およびそれらの使用方法 |
ES2901627T3 (es) | 2009-06-10 | 2022-03-23 | Arbutus Biopharma Corp | Formulación lipídica mejorada |
CN104651408A (zh) | 2009-06-15 | 2015-05-27 | 阿尔尼拉姆医药品有限公司 | 靶向pcsk9基因的脂质配制的dsrna |
EP2451823A4 (fr) | 2009-07-06 | 2013-07-03 | Alnylam Pharmaceuticals Inc | Compositions et procédés pour améliorer la production d'un produit biologique |
WO2011005861A1 (fr) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | Coiffes dextrémité doligonucléotides |
WO2011005860A2 (fr) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | Mimétiques de 5' phosphate |
EP2454369A4 (fr) | 2009-07-16 | 2013-07-03 | Isis Pharmaceuticals Inc | Modulation de l expression du facteur 7 |
EP2462153B1 (fr) | 2009-08-06 | 2015-07-29 | Isis Pharmaceuticals, Inc. | Analogues d'acides nucléiques cyclohexoses bicycliques |
WO2011019839A2 (fr) * | 2009-08-12 | 2011-02-17 | The Medicines Company | Antibiotiques glycopeptides et lipoglycopeptides à solubilité améliorée |
TWI458493B (zh) | 2009-09-25 | 2014-11-01 | Iner Aec Executive Yuan | 新穎肝標靶藥劑與合成方法 |
JP5892938B2 (ja) | 2009-10-16 | 2016-03-30 | グラクソ グループ リミテッドGlaxo Group Limited | Hbvアンチセンス阻害剤 |
TWI391144B (zh) | 2009-10-26 | 2013-04-01 | Iner Aec Executive Yuan | 一種定量肝殘餘功能的檢驗方法與其新穎肝受體造影檢驗藥劑 |
TWI388338B (zh) | 2009-10-26 | 2013-03-11 | Iner Aec Executive Yuan | 對聚合醣鏈進行放射標誌以作為肝受體造影劑之方法 |
EP2496238A4 (fr) * | 2009-11-03 | 2013-10-02 | Alnylam Pharmaceuticals Inc | Compositions de lipides formulés et procédés pour l'inhibition de l'expression de transthyrétine (ttr) |
WO2011072290A2 (fr) | 2009-12-11 | 2011-06-16 | The Regents Of The University Of Michigan | Conjugués de médicament dendrimère ciblés |
CN111700901A (zh) | 2010-01-08 | 2020-09-25 | Ionis制药公司 | 血管生成素样3表达的调节 |
US9198972B2 (en) | 2010-01-28 | 2015-12-01 | Alnylam Pharmaceuticals, Inc. | Monomers and oligonucleotides comprising cycloaddition adduct(s) |
EA024534B1 (ru) | 2010-02-24 | 2016-09-30 | Эрроухэд Рисерч Корпорейшн | КОНЪЮГИРОВАННАЯ СИСТЕМА ДОСТАВКИ И КОМПОЗИЦИЯ ДЛЯ НАПРАВЛЕННОЙ ДОСТАВКИ МАЛЫХ ИНТЕРФЕРИРУЮЩИХ РНК (миРНК) И СПОСОБ ПОЛУЧЕНИЯ КОМПОЗИЦИИ |
US9193752B2 (en) | 2010-03-17 | 2015-11-24 | Isis Pharmaceuticals, Inc. | 5′-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom |
EP2553019A1 (fr) | 2010-03-26 | 2013-02-06 | Mersana Therapeutics, Inc. | Polymères modifiés pour l'administration de polynucléotides, procédé de fabrication, et procédés d'utilisation de ceux-ci |
US20130109817A1 (en) | 2010-03-26 | 2013-05-02 | Mersana Therapeutics, Inc. | Modified Polymers for Delivery of Polynucleotides, Method of Manufacture, and Methods of Use Thereof |
WO2011123621A2 (fr) | 2010-04-01 | 2011-10-06 | Alnylam Pharmaceuticals Inc. | Monomères modifiés en 2' et 5' et oligonucléotides |
US9725479B2 (en) | 2010-04-22 | 2017-08-08 | Ionis Pharmaceuticals, Inc. | 5′-end derivatives |
WO2011133876A2 (fr) | 2010-04-22 | 2011-10-27 | Alnylam Pharmaceuticals, Inc. | Oligonucléotides comprenant des nucléosides acycliques et abasiques, et analogues |
US9127033B2 (en) | 2010-04-28 | 2015-09-08 | Isis Pharmaceuticals, Inc. | 5′ modified nucleosides and oligomeric compounds prepared therefrom |
JP6005628B2 (ja) | 2010-04-28 | 2016-10-12 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | 修飾ヌクレオシド、その類似体、およびこれらから調製されるオリゴマー化合物 |
BR112012027547B1 (pt) | 2010-04-29 | 2022-06-14 | Ionis Pharmaceuticals, Inc | Oligonucleotídeo modificado de fita simples, composição, e seus usos para tratar amiloidose transtirretina, reduzir os seus sintomas e para reduzir a expressão de mrna ou de proteína de transtirretina |
US20130236968A1 (en) | 2010-06-21 | 2013-09-12 | Alnylam Pharmaceuticals, Inc. | Multifunctional copolymers for nucleic acid delivery |
WO2012037254A1 (fr) | 2010-09-15 | 2012-03-22 | Alnylam Pharmaceuticals, Inc. | Agents à base d'arni modifiés |
WO2012067970A2 (fr) | 2010-11-11 | 2012-05-24 | Ted M Dawson | Répression transcriptionnelle conduisant à la maladie de parkinson |
EP2640400A4 (fr) | 2010-11-19 | 2016-01-20 | Sirna Therapeutics Inc | Polymères poly(amide) destinés à l'administration d'oligonucléotides |
US8501930B2 (en) | 2010-12-17 | 2013-08-06 | Arrowhead Madison Inc. | Peptide-based in vivo siRNA delivery system |
AU2011343664B2 (en) | 2010-12-17 | 2015-10-08 | Arrowhead Pharmaceuticals, Inc. | Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA |
WO2012089352A1 (fr) | 2010-12-29 | 2012-07-05 | F. Hoffmann-La Roche Ag | Conjugués de petites molécules pour l'administration intracellulaire d'acides nucléiques |
WO2012109395A1 (fr) | 2011-02-08 | 2012-08-16 | Isis Pharmaceuticals, Inc. | Composés oligomères comprenant des nucléotides bicycliques et leurs utilisations |
JP5943993B2 (ja) | 2011-04-01 | 2016-07-05 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | 転写のシグナル伝達及び活性化因子3(stat3)発現の調節 |
AU2012242642A1 (en) * | 2011-04-13 | 2013-05-02 | Ionis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
EP3312189A1 (fr) | 2011-04-21 | 2018-04-25 | Ionis Pharmaceuticals, Inc. | Modulation de l'expression du virus de l'hépatite b (vhb) |
TW201303013A (zh) | 2011-04-21 | 2013-01-16 | Isis Pharmaceuticals Inc | B型肝炎病毒(hbv)表現之調節 |
AU2012249324B2 (en) | 2011-04-27 | 2016-10-06 | Ionis Pharmaceuticals, Inc. | Modulation of apolipoprotein CIII (ApoCIII) expression |
WO2012174154A1 (fr) | 2011-06-13 | 2012-12-20 | Isis Pharmaceuticals, Inc. | Modulation de réponses inflammatoires par le facteur vii |
EP2721156B1 (fr) | 2011-06-16 | 2016-12-21 | Ionis Pharmaceuticals, Inc. | Modulation antisens de l'expression du récepteur 4 du facteur de croissance fibroblastique |
MX344807B (es) | 2011-06-21 | 2017-01-09 | Alnylam Pharmaceuticals Inc | Composiciones y metodos para inhibicion de genes para alipoproteina c-iii (apoc3). |
BR112013033260B1 (pt) * | 2011-06-21 | 2022-06-21 | Alnylam Pharmaceuticals | Ácido ribonucleico de fita dupla (dsrna) para inibir a expressão de angptl3, composição farmacêutica e método in vitro para inibir a expressão de angptl3 em uma célula |
WO2012177639A2 (fr) | 2011-06-22 | 2012-12-27 | Alnylam Pharmaceuticals, Inc. | Biotraitement et bioproduction à l'aide de lignées de cellules aviaires |
US20130017250A1 (en) | 2011-07-15 | 2013-01-17 | The Trustees Of Columbia University In The City Of New York | Methods For High Density Lipoprotein Cholesterol Regulation |
AU2012300476B2 (en) | 2011-08-26 | 2016-03-24 | Arrowhead Research Corporation | Poly(vinyl ester) polymers for in vivo nucleic acid delivery |
DK2751270T3 (en) | 2011-08-29 | 2018-10-29 | Ionis Pharmaceuticals Inc | OLIGOMER-CONJUGATE COMPLEXES AND THEIR USE |
MX353322B (es) | 2011-09-20 | 2018-01-05 | Ionis Pharmaceuticals Inc | Modulacion antisentido de la expresion de gcgr. |
EP2771463A4 (fr) | 2011-10-25 | 2015-09-09 | Isis Pharmaceuticals Inc | Modulation antisens de l'expression de gccr |
BR112014011896B1 (pt) | 2011-11-18 | 2021-01-19 | Alnylam Pharmaceuticals, Inc. | Agentes de rnai, composições, método de inibição de expressão de uma transtirretina(ttr), uso destes agentes, e kits |
AU2013216852A1 (en) | 2012-02-08 | 2014-08-21 | Isis Pharmaceuticals, Inc. | Methods and compositions for modulating Factor VII expression |
US9340784B2 (en) | 2012-03-19 | 2016-05-17 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating alpha-1-antitrypsin expression |
WO2013142571A2 (fr) | 2012-03-20 | 2013-09-26 | Cornell University | Dosages pour l'identifications de composés qui modulent l'homéostasie lipidique |
US9133461B2 (en) | 2012-04-10 | 2015-09-15 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the ALAS1 gene |
WO2013159109A1 (fr) | 2012-04-20 | 2013-10-24 | Isis Pharmaceuticals, Inc. | Modulation de l'expression du virus de l'hépatite b (hbv) |
WO2013159108A2 (fr) | 2012-04-20 | 2013-10-24 | Isis Pharmaceuticals, Inc. | Composés oligomères comprenant des nucléotides bicycliques et utilisations de ceux-ci |
US20150299696A1 (en) | 2012-05-02 | 2015-10-22 | Sirna Therapeutics, Inc. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
TW201808342A (zh) | 2012-05-02 | 2018-03-16 | 喜納製藥公司 | 包含四galnac之新穎結合物及傳送寡核苷酸之方法 |
US20160002624A1 (en) | 2012-05-17 | 2016-01-07 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide compositions |
US9574193B2 (en) | 2012-05-17 | 2017-02-21 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating apolipoprotein (a) expression |
PT2855500T (pt) | 2012-05-24 | 2020-09-24 | Ionis Pharmaceuticals Inc | Métodos e composições para modular a expressão de apolipoproteína(a) |
WO2013192233A1 (fr) | 2012-06-18 | 2013-12-27 | Isis Pharmaceuticals, Inc. | Composés et procédé pour capture cellulaire améliorée de composés antisens |
AU2013299717B2 (en) | 2012-08-06 | 2018-06-28 | Alnylam Pharmaceuticals, Inc. | Carbohydrate conjugated RNA agents and process for their preparation |
US9695418B2 (en) | 2012-10-11 | 2017-07-04 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleosides and uses thereof |
BR112015010116A2 (pt) | 2012-11-15 | 2017-08-22 | Roche Innovation Ct Copenhagen As | COMPOSTOS CONJUGADOS ANTI-SENTIDO ANTI-ApoB |
WO2014118272A1 (fr) | 2013-01-30 | 2014-08-07 | Santaris Pharma A/S | Conjugués glucidiques d'oligonucléotides antimir-22 |
EP2951305B1 (fr) | 2013-01-30 | 2018-08-15 | F.Hoffmann-La Roche Ag | Conjugués glucidiques d'oligonucléotides d'acides nucléiques bloqués |
MX2015015239A (es) | 2013-05-01 | 2016-10-03 | Ionis Pharmaceuticals Inc | Composiciones y metodos. |
CA2912345C (fr) | 2013-05-16 | 2020-10-06 | Sumitomo Dainippon Pharma Co., Ltd. | Adjuvant de transplantation en therapie cellulaire utilisant des cellules neurales progenitrices |
WO2014205451A2 (fr) | 2013-06-21 | 2014-12-24 | Isis Pharmaceuticals, Inc. | Compositions et méthodes pour moduler des acides nucléiques cibles |
RS59986B1 (sr) | 2013-06-27 | 2020-03-31 | Roche Innovation Ct Copenhagen As | Antisens oligomeri i konjugati koji ciljno deluju na pcsk9 |
RU2700244C2 (ru) | 2013-07-02 | 2019-09-13 | Ионис Фармасьютикалз, Инк. | Модуляторы рецептора гормона роста |
US10808246B2 (en) | 2013-07-11 | 2020-10-20 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
EP3603677A1 (fr) | 2013-09-13 | 2020-02-05 | Ionis Pharmaceuticals, Inc. | Modulateurs du facteur b du complément |
WO2015042447A1 (fr) | 2013-09-20 | 2015-03-26 | Isis Pharmaceuticals, Inc. | Nucléosides thérapeutiques ciblées et leur utilisation |
CA2928349A1 (fr) | 2013-11-14 | 2015-05-21 | Roche Innovation Center Copenhagen A/S | Composes conjugues antisens apob |
AU2014360314B2 (en) | 2013-12-06 | 2018-04-26 | Dicerna Pharmaceuticals, Inc. | Methods and compositions for the specific inhibition of transthyretin (TTR) by double-stranded RNA |
BR112016022855B1 (pt) | 2014-05-01 | 2022-08-02 | Ionis Pharmaceuticals, Inc | Compostos e composições para modular a expressão de pkk e seus usos |
RS59182B1 (sr) | 2014-05-01 | 2019-10-31 | Ionis Pharmaceuticals Inc | Kompozicije i postupci za modulaciju ekspresije faktora b komplementa |
CA2946003A1 (fr) | 2014-05-01 | 2015-11-05 | Ionis Pharmaceuticals, Inc. | Compositions et methodes de modulation de l'expression de l'angiopoietine de type 3 |
EP3811977A1 (fr) | 2014-05-01 | 2021-04-28 | Ionis Pharmaceuticals, Inc. | Procédé de synthèse de grappes de conjugués réactifs |
EP3974534A1 (fr) | 2014-05-01 | 2022-03-30 | Ionis Pharmaceuticals, Inc. | Compositions et procédés pour moduler l'expression du récepteur de l'hormone de croissance |
WO2015179693A1 (fr) | 2014-05-22 | 2015-11-26 | Isis Pharmaceuticals, Inc. | Composés antisens conjugués et leur utilisation |
US20170145424A1 (en) | 2014-06-06 | 2017-05-25 | Ionis Pharmaceuticals, Inc. | Compositions and methods for enhanced intestinal absorption of conjugated oligomeric compounds |
PE20181180A1 (es) * | 2015-11-06 | 2018-07-20 | Ionis Pharmaceuticals Inc | MODULAR LA EXPRESION DE APOLIPOPROTEINA (a) |
DK4119569T3 (da) * | 2015-11-06 | 2024-08-12 | Ionis Pharmaceuticals Inc | Konjugerede antisense-forbindelser til anvendelse i behandling |
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US11759532B2 (en) | 2019-12-17 | 2023-09-19 | Shenzhen Rhegen Biotechnology Co., Ltd. | mRNA targeting molecule comprising N-acetylgalactosamine binding polypeptide and preparation method therefor |
US11707528B2 (en) | 2020-07-01 | 2023-07-25 | Shenzhen Rhegen Biotechnology Co., Ltd. | Mannose-based mRNA targeted delivery system and use thereof |
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